Processes for producing 7-isoindolinequinolonecarboxylic derivatives and intermediates therefor, salts of 7-isoindolinequinolonecarboxylic acids, hydrates thereof, and composition containing the same as active ingredient

ABSTRACT

This invention relates to processes for producing a 7-isoindoline-quinolonecarboxylic acid derivative represented by the general formula [1] which is useful as an antibacterial agent, and an intermediate thereof:                    
     wherein R 1  represents a hydrogen atom or a carboxyl-protecting group; R 2  represents a substituted or unsubstituted alkyl, alkenyl, cycloalkyl, aryl or heterocyclic group; R 3  represents at least one group selected from hydrogen atom, halogen atoms, substituted or unsubstituted alkyl, alkenyl, cycloalkyl, aryl, alkoxy or alkylthio groups, nitro group, cyano group, acyl groups, protected or unprotected hydroxyl groups and protected or unprotected or substituted or unsubstituted amino groups; R 4  represents at least one group selected from hydrogen atom, halogen atoms, substituted or unsubstituted alkyl, alkenyl, cycloalkyl, aralkyl, aryl, alkoxy or alkylthio groups, protected or unprotected hydroxyl or imino groups, protected or unprotected or substituted or unsubstituted amino groups, alkylidene groups, oxo group and groups each forming a cycloalkane group together with the carbon atom to which R 4  bonds; R 5  represents a hydrogen atom, an amino-protecting group, a substituted or unsubstituted alkyl, cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl or aryl group; R 6  represents a hydrogen atom, a halogen atom, a substituted or unsubstituted alkyl, alkoxy or alkylthio group, a protected or unprotected hydroxyl or amino group or a nitro group; and A represents CH or C—R 7  in which R 7  represents a halogen atom, a substituted or unsubstituted alkyl, alkoxy or alkylthio group or a protected or unprotected hydroxyl group, and to a salt of a 7-isoindoline-quinolonecarboxylic acid represented by the general formula [1], a hydrate thereof and a composition comprising them as an active ingredient.

This application is a 371 of PCT/JP98/04854, filed Oct. 27, 1998.

TECHNICAL FIELD

This invention relates to processes for producing a7-isoindoline-quinolonecarboxylic acid derivative represented by thegeneral formula [1] and its intermediate as well as a salt of7-isoindoline-quinolonecarboxylic acid derivative represented by thegeneral formula [1], its hydrate and a composition comprising the sameas an active ingredient:

wherein R¹ represents a hydrogen atom or a carboxyl-protecting group; R²represents a substituted or unsubstituted alkyl, alkenyl, cycloalkyl,aryl or heterocyclic group; R³ represents at least one group selectedfrom hydrogen atom, halogen atoms, substituted or unsubstituted alkyl,alkenyl, cycloalkyl, aryl, alkoxy or alkylthio groups, nitro group,cyano group, acyl groups, protected or unprotected hydroxyl groups andprotected or unprotected or substituted or unsubstituted amino groups;R⁴ represents at least one group selected from hydrogen atom, halogenatoms, substituted or unsubstituted alkyl, alkenyl, cycloalkyl, aralkyl,aryl, alkoxy or alkylthio groups, protected or unprotected hydroxyl orimino groups, protected or unprotected or substituted or unsubstitutedamino groups, alkylidene groups, oxo group and groups each forming acycloalkane ring with the carbon atom to which R⁴ bonds; R⁵ represents ahydrogen atom, an amino-protecting group or a substituted orunsubstituted alkyl, cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl oraryl group; R⁶ represents a hydrogen atom, a halogen atom, a substitutedor unsubstituted alkyl, alkoxy or alkylthio group, a protected orunprotected hydroxyl or amino group or a nitro group; and A representsCH or C—R⁷ in which R⁷ represents a halogen atom, a substituted orunsubstituted alkyl, alkoxy or alkylthio group or a protected orunprotected hydroxyl group.

BACKGROUND ART

As the process for producing a compound of the general formula [1],there has been known the process described in WO97/29102. That is tosay, said publication describes that a compound of the general formula[1] can be produced by subjecting a 5-halogenoisoindoline derivativerepresented by the following general formula [4] or its salt:

wherein R³, R⁴ and R⁵ have the same meanings as mentioned above and X¹represents a halogen atom, to lithiation or Grignard reaction andthereafter to reaction with a trialkyl borate to form anisoindoline-5-boronic acid derivative represented by the followinggeneral formula [2c] or its salt:

wherein R³, R⁴ and R⁵ have the same meanings as mentioned above and R¹¹represents a hydrogen atom or an alkyl group; and subsequently reactingthe isoindoline-5-boronic acid derivative or its salt with a7-halogenoquinolonecarboxylic acid represented by the following generalformula [3b]:

wherein R¹, R², R⁶ and A have the same meanings as mentioned above andX³ represents a halogen atom, in the presence of a palladium complexsuch as bis(triphenylphosphine)-palladium(II) chloride,tetrakis(triphenylphosphine)-palladium(0) or the like.

Among the compounds of the general formula [1],(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinoline-carboxylicacid represented by the formula:

(referred to hereinafter as T-3811) is a compound excellent in activityagainst Gram-positive and Gram-negative bacteria and the development ofa process for industrially producing the same has been desired.

Moreover, T-3811 is low in solubility in the vicinity of neutral, sothat the enhancement of solubility at a physiologically acceptable pHhas been desired.

DISCLOSURE OF THE INVENTION

In order to develop a process for industrially producing a7-isoindoline-quinolonecarboxylic acid derivative of the general formula[1] including T-3811, the present inventors have diligently maderesearch to find consequently that a coupling reaction between anisoindoline-5-boronic acid derivative represented by the followinggeneral formula [2]:

wherein R³, R⁴ and R⁵ have the same meanings as mentioned above and R⁸and R⁹ represent hydrogen atoms or lower alkyl groups or form a ringcomprising the boron atom when taken together, and a 7-leavinggroup-substituted quinolone-carboxylic acid represented by the followinggeneral formula [3]:

wherein R¹, R², R⁶ and A have the same meanings as mentioned above andX² represents a leaving group, can be easily carried out in the presenceof metallic palladium.

Furthermore, it has been found that an isoindoline-5-boronic acidderivative represented by the following general formula [2a]:

wherein R³, R⁴ and R⁵ have the same meanings as mentioned above and Zrepresents an alkylene group can easily be obtained not by theconventional borodation through lithiation or Grignard reaction but bythe reaction of a 5-halogenoisoindoline derivative represented by thefollowing general formula [4]:

wherein R³, R⁴, R⁵ and X¹ have the same meanings as mentioned above,with a dialkoxyborane or an alkoxydiborane in the presence of apalladium catalyst, and further found that the compound of the generalformula [2a] can be applied, without being isolated, to the so-calledone-pot reaction by which the compound of the general formula [3] isreacted to produce a 7-isoindoline-quinolonecarboxylic acid derivativerepresented by the general formula [1].

Also, the present inventors have found that a1-alkylisoindoline-5-boronic acid derivative represented by thefollowing general formula [2b]:

wherein R^(4a) represents an alkyl group and R⁵, R⁸ and R⁹ have the samemeanings as mentioned above is an excellent intermediate for producing a7-isoindoline-quinolone-carboxylic acid derivative represented by thefollowing general formula [1a]:

wherein R^(4a), R¹, R², R⁵, R⁶ and A have the same meanings as mentionedabove among the compounds of the general formula [1].

Moreover, it has been found that a 1-alkyl-5-halogenoisoindolinederivative represented by the following general formula [4a]:

wherein R^(4a), R⁵ and X¹ have the same meanings as mentioned above, canbe produced by using a 4-halogenobenzylamine derivative as the startingmaterial.

Furthermore, it has been found that as the process for producing a7-bromo-quinolonecarboxylic acid derivative represented by the followinggeneral formula [3a] which is a useful intermediate for producingT-3811:

wherein R^(1b) represents a carboxyl-protecting group; R^(7a) representsa substituted or unsubstituted alkyl group; and R^(2a) represents asubstituted or unsubstituted alkyl, cycloalkyl, aryl or heterocyclicgroup, a process in which a 2,4-dibromo-3-hydroxybenzoic acid ester isused as the starting material and which is through various intermediatesas mentioned hereinafter is an excellent industrial production process.

As mentioned above, the present inventors have diligently made researchon 7-isoindoline-quinolone-carboxylic acid derivatives represented bythe general formula [1] including T-3811 and intermediates for producingthe same and have accomplished this invention.

In addition, the present inventors have examined various salts of T-3811which have never been known, and have consequently found that amongthem, methanesulfonate of T-3811 is much higher in solubility at aphysiologically acceptable pH than the other salts of T-3811 and furtherthat T-3811 methanesulfonate hydrate has no polymorphism and is good instability against humidity, and hence, it has a very high usefulness asa composition, particularly as a starting material for preparation,whereby this invention has been accomplished.

In the present specification, unless otherwise specified, the term“halogen atom” means fluorine atom, chlorine atom, bromine atom oriodine atom; the term “alkyl group” means a straight or branched chainC₁₋₁₀ alkyl group, for example, methyl, ethyl, n-propyl, isopropyl,n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl, hexyl, heptyl, octylor the like; the term “alkenyl group” means a straight or branched chainC₂₋₁₀ alkenyl group, for example, vinyl, allyl, isopropenyl, butenyl,pentenyl, hexenyl, heptenyl, octenyl or the like; the term “alkylidenegroup” means a straight or branched chain C₁₋₁₀ alkylidene group, forexample, methylene, ethylidene, propylidene, isopropylidene, butylidene,hexylidene, octylidene or the like; the term “cycloalkyl group” means aC₃₋₆ cycloalkyl group, for example, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl or the like; the term “cycloalkane ring” means aC₃₋₆ cycloalkane ring, for example, cyclopropane, cyclobutane,cyclopentane, cyclohexane or the like; the term “alkylene group” means astraight or branched chain C₁₋₁₀ alkylene group, for example, ethylene,trimethylene, tetramethylene, 1,2-dimethylethylene,1,3-dimethyl-trimethylene, 1,1,2,2-tetramethylethylene or the like; theterm “alkoxy group” means a straight or branched chain C₁₋₁₀ alkoxygroup, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,isobutoxy, sec-butoxy, tert-butoxy, pentyloxy, hexyloxy, heptyloxy,octyloxy or the like; the term “alkoxycarbonyl group” means analkoxy-CO— group (in which the alkoxy represents the above-mentionedstraight or branched chain C₁₋₁₀ alkoxy group), for example,methoxycarbonyl, ethoxycarbonyl, n-propoxycarbonyl, isopropoxycarbonyl,n-butoxycarbonyl, isobutoxycarbonyl, sec-butoxycarbonyl,tert-butoxycarbonyl, pentyloxycarbonyl or the like; the term “alkylaminogroup” means a straight or branched chain C₁₋₁₀ alkyl group-substitutedamino group, for example, methylamino, ethylamino, propylamino,butylamino, pentylamino, hexylamino, dimethylamino, diethylamino,methylethylamino, dipropylamino, dibutylamino, dipentylamino or thelike; the term “alkylthio group” means a straight or branched chainC₁₋₁₀ alkylthio group, for example, methylthio, ethylthio, n-propylthio,isopropylthio, n-butylthio, isobutylthio, sec-butylthio, tertbutylthio,pentylthio, hexylthio, heptylthio, octylthio or the like; the term“alkylsulfonyl group” means a straight or branched C₁₋₁₀ alkylsulfonylgroup, for example, methylsulfonyl, ethylsulfonyl, n-propylsulfonyl,isopropylsulfonyl, n-butylsulfonyl, isobutylsulfonyl, sec-butylsulfonyl,tert-butylsulfonyl, pentylsulfonyl, hexylsulfonyl, heptylsulfonyl,octylsulfonyl or the like; the term “acyl group” means, for example, aformyl group, a straight or branched chain C₂₋₅ alkanoyl group such asacetyl, ethylcarbonyl or the like or an aroyl group such as benzoyl,naphthylcarbonyl or the like; the term “aryl group” means, for example,a phenyl or naphthyl group; the term “arylsulfonyl group” means, forexample, a phenylsulfonyl or naphthylsulfonyl group; the term “aralkylgroup” means, for example, a benzyl, phenethyl, diphenylmethyl ortriphenylmethyl group; the term “heterocyclic group” means a 4-membered,5-membered or 6-membered ring containing at least one hetero atomselected from oxygen atom, nitrogen atom and sulfur atom as the heteroatom forming the ring or a condensed ring thereof, for example, anoxetanyl, thietanyl, azetidinyl, furyl, pyrrolyl, thienyl, oxazolyl,isoxazolyl, imidazolyl, thiazolyl, isothiazolyl, pyrrolidinyl,benzofuranyl, benzothiazolyl, pyridyl, quinolyl, pyrimidinyl ormorpholinyl group.

Moreover, in the present specification, the term “lower” means 1 to 5carbon atoms, provided that the term “lower” in the term “lower alkenyl”means 2 to 5 carbon atoms.

The protecting groups for amino group, lower alkylamino group and iminogroup include all conventional groups usable as amino-protecting groups,and there are mentioned, for example, acyl groups such astrichloroethoxycarbonyl, tribromoethoxycarbonyl, benzyloxycarbonyl,p-nitrobenzyloxycarbonyl, o-bromobenzyloxycarbonyl, (mono-, di-,tri-)chloroacetyl, trifluoroacetyl, phenylacetyl, formyl, acetyl,benzoyl, tert-amyloxycarbonyl, tert-butoxycarbonyl,p-methoxybenzyloxycarbonyl, 3,4-dimethoxy-benzyloxycarbonyl,4-(phenylazo)benzyloxycarbonyl, 2-furfuryloxycarbonyl,diphenylmethoxycarbonyl, 1,1-dimethylpropoxycarbonyl,isopropoxycarbonyl, phthaloyl, succinyl, alanyl, leucyl,1-adamantyloxycarbonyl, 8-quinolyloxycarbonyl, pivaloyl and the like;ar-lower alkyl groups such as benzyl, diphenylmethyl, trityl and thelike; arylthio groups such as 2-nitrophenylthio, 2,4-dinitrophenylthioand the like; alkyl- or aryl-sulfonyl groups such as methanesulfonyl,p-toluenesulfonyl and the like; di-lower alkylamino-lower alkylidenegroups such as N,N-dimethylaminomethylene and the like; ar-loweralkylidene groups such as benzylidene, 2-hydroxybenzylidene,2-hydroxy-5-chlorobenzylidene, 2-hydroxy-1-naphthylmethylene and thelike; nitrogen-containing heterocyclic alkylidene groups such as3-hydroxy-4-pyridylmethylene and the like; cycloalkylidene groups suchas cyclohexylidene, 2-ethoxycarbonylcyclohexylidene,2-ethoxycarbonylcyclopentylidene, 2-acetylcyclohexylidene,3,3-dimethyl-5-oxycyclohexylidene and the like; diaryl- or di-ar-loweralkyl-phosphoryl groups such as diphenylphosphoryl, dibenzylphosphoryland the like; oxygen-containing heterocyclic alkyl groups such as5-methyl-2-oxo-2H-1,3-dioxol-4-yl-methyl and the like; substituted silylgroups such as trimethylsilyl and the like; etc.

The protecting groups for the carboxyl group include all conventionalgroups usable as carboxyl-protecting groups and there are mentioned, forexample, lower alkyl groups such as methyl, ethyl, n-propyl, isopropyl,1,1-dimethylpropyl, n-butyl, tert-butyl and the like; aryl groups suchas phenyl, naphthyl and the like; ar-lower alkyl groups such as benzyl,diphenylmethyl, trityl, p-nitrobenzyl, p-methoxybenzyl,bis(p-methoxy-phenyl)methyl and the like; acyl-lower alkyl groups suchas acetylmethyl, benzoylmethyl, p-nitrobenzoylmethyl,p-bromo-benzoylmethyl, p-methanesulfonylbenzoylmethyl and the like;oxygen-containing heterocyclic groups such as 2-tetra-hydropyranyl,2-tetrahydrofuranyl and the like; halogeno-lower alkyl groups such as2,2,2-trichloroethyl and the like; lower alkylsilyl-lower alkyl groupssuch as 2-(trimethylsilyl)ethyl and the like; acyloxy-lower alkyl groupssuch as acetoxymethyl, propionyloxymethyl, pivaloyloxymethyl and thelike; nitrogen-containing heterocyclic-lower alkyl groups such asphthalimidomethyl, succinimidomethyl and the like; cycloalkyl groupssuch as cyclohexyl and the like; lower alkoxy-lower alkyl groups such asmethoxymethyl, methoxyethoxymethyl, 2-(trimethyl-silyl)ethoxymethyl andthe like; ar-lower alkoxy-lower alkyl groups such as benzyloxymethyl andthe like; lower alkylthio-lower alkyl groups such as methylthiomethyl,2-methylthioethyl and the like; arylthio-lower alkyl groups such asphenylthiomethyl and the like; lower alkenyl groups such as1,1-dimethyl-2-propenyl, 3-methyl-3-butenyl, allyl and the like;substituted silyl groups such as trimethylsilyl, triethylsilyl,triisopropylsilyl, diethylisopropylsilyl, tert-butyldimethylsilyl,tert-butyldiphenylsilyl, diphenylmethylsilyl,tert-butylmethoxyphenylsilyl and the like.

The protecting groups for the hydroxyl group include all conventionalgroups usable as hydroxyl-protecting groups and there are mentioned, forexample, acyl groups such as benzyloxycarbonyl,4-nitrobenzyloxycarbonyl, 4-bromobenzyloxycarbonyl,4-methoxybenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl,methoxycarbonyl, ethoxycarbonyl, tert-butoxycarbonyl,1,1-dimethylpropoxycarbonyl, isopropoxycarbonyl, isobutyloxycarbonyl,diphenylmethoxycarbonyl, 2,2,2-trichloroethoxycarbonyl,2,2,2-tribromoethoxycarbonyl, 2-(trimethylsilyl)-ethoxycarbonyl,2-(phenylsulfonyl)ethoxycarbonyl, 2-(triphenylphosphonio)ethoxycarbonyl,2-furfuryloxycarbonyl, 1-adamantyloxycarbonyl, vinyloxycarbonyl,allyloxycarbonyl, S-benzylthiocarbonyl, 4-ethoxy-1-naphthyloxycarbonyl,8-quinolyloxycarbonyl, acetyl, formyl, chloroacetyl, dichloroacetyl,trichloroacetyl, trifluoroacetyl, methoxyacetyl, phenoxyacetyl,pivaloyl, benzoyl and the like; lower alkyl groups such as methyl,tert-butyl, 2,2,2-trichloroethyl, 2-trimethylsilylethyl and the like;lower alkenyl groups such as allyl and the like; ar-lower alkyl groupssuch as benzyl, p-methoxybenzyl, 3,4-dimethoxybenzyl, diphenylmethyl,trityl and the like; oxygen-containing and sulfur-containingheterocyclic groups such as tetrahydrofuryl, tetrahydropyranyl,tetrahydrothio-pyranyl and the like; lower alkoxy- and loweralkylthiolower alkyl groups such as methoxymethyl, methylthiomethyl,benzyloxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl,2-(trimethylsilyl)ethoxymethyl, 1-ethoxyethyl, 1-methyl-1-methoxyethyland the like; lower alkyl- and aryl-sulfonyl groups such asmethanesulfonyl, p-toluenesulfonyl and the like; substituted silylgroups such as trimethylsilyl, triethylsilyl, triisopropylsilyl,diethylisopropylsilyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl,diphenylmethylsilyl, tert-butylmethoxy-phenylsilyl and the like; etc.

The substituent of the alkyl, alkenyl, cycloalkyl, aryl or heterocyclicgroup for R²; the substituent of the alkyl, alkenyl, cycloalkyl, aryl,alkoxy, alkylthio or amino group for R³; the substituent of the alkyl,alkenyl, cycloalkyl, aralkyl, aryl, alkoxy, alkylthio or amino group forR⁴; the substituent of the alkyl, cycloalkyl, alkyl-sulfonyl,arylsulfonyl, acyl or aryl group for R⁵; the substituent of the alkyl,alkoxy or alkylthio group for R⁶; the substituent of the alkyl, alkoxyor alkylthio group for R⁷; and the substituent of the alkyl for R^(7a)include halogen atoms, cyano group, protected or unprotected carboxylgroups, protected or unprotected hydroxyl groups, protected orunprotected amino groups, protected or unprotected lower alkylaminogroups, lower alkyl groups, lower alkoxy groups, lower alkoxycarbonylgroups, aryl groups, cycloalkyl groups, lower alkenyl groups and halogenatom-substituted lower alkyl groups, and the R², R³, R⁴, R⁵, R⁶, R⁷ andR^(7a) groups may be substituted by one or two or more of these groups.

Moreover, as the substituent of the alkyl for R^(7a), a halogen atom ispreferable.

The ring comprising the boron atom which R⁸ and R⁹ form when takentogether includes 5-membered to 8-membered rings containing at least onehetero atom selected from oxygen atom and nitrogen atom as the heteroatom forming the ring and condensed rings thereof, for example,1,3,2-dioxaborolane, 1,3,2-dioxaborinane, 1,3,5,2-dioxazaborinane,1,3,5,2-trioxaborinane, 1,3,6,2-trioxaborocane, 1,3,6,2-dioxazaborocaneand the like.

The leaving group for X² includes halogen atoms such as chlorine atom,bromine atom, iodine atom and the like; halogen-substituted orunsubstituted alkylsulfonyloxy groups such as methylsulfonyloxy,trifluoromethyl-sulfonyloxy and the like; and arylsulfonyloxy groupssuch as p-fluorophenylsulfonyloxy and the like.

As the alkyl group for R^(4a), a lower alkyl group is preferable.

I. Process for Producing Compound of the General formula [1] and Processfor Producing Compound of the General Formula [2a]

Production Process IA

Production Process IB

wherein R¹, R², R³, R⁴, R⁵, R⁶, R⁸, R⁹, X¹, X², A and Z have the samemeanings as mentioned above.

The compounds of the general formulas [1], [2], [2a], [3], [4], [5a] and[5b] may be in the form of salts. As the salts, there can be mentionedusually known salts at basic groups such as amino group and the like andat acidic groups such as hydroxyl group, carboxyl group and the like. Asthe salts at basic groups, there can be mentioned, for example, saltswith mineral acids such as hydrochloric acid, hydrobromic acid, sulfuricacid and the like; salts with organic carboxylic acids such as tartaricacid, formic acid, lactic acid, citric acid, trichloroacetic acid,trifluoroacetic acid and the like; and salts with sulfonic acids such asmethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,mesitylenesulfonic acid, naphthalenesulfonic acid and the like.Moreover, the salts at acidic groups, there can be mentioned, forexample, salts with alkali metals such as sodium, potassium and thelike; salts with alkaline earth metals such as calcium, magnesium andthe like; salts with ammonium; salts with nitrogen-containing organicbases such as trimethylamine, triethylamine, tributylamine, pyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,diethylamine, dicyclohexylamine, procaine, dibenzylamine,N-benzyl-b-phenethylamine, 1-ephenamine, N,N′-dibenzylethylenediamineand the like; etc.

Production Process IA

(1) Process for Producing Compound of the General Formula [1] or itsSalt

The compound of the general formula [1] or its salt can be produced bysubjecting a compound of the general formula [2] or its salt and acompound of the general formula [3] or its salt to coupling reactionusing metallic palladium in the presence or absence of a base.

The solvent which is used in this reaction is not particularly limitedas far as it does not adversely affect the reaction, and includes, forexample, water; alcohols such as methanol, ethanol, propanol and thelike; aromatic hydrocarbons such as benzene, toluene, xylene and thelike; halogenated hydrocarbons such as methylene chloride, chloroform,dichloroethane and the like; ethers such as dioxane, tetrahydrofuran,anisole, diethylene glycol diethyl ether, dimethyl Cellosolve and thelike; esters such as ethyl acetate, butyl acetate and the like; ketonessuch as acetone, methyl ethyl ketone and the like; nitrites such asacetonitrile and the like; amides such as N,N-dimethylformamide,N,N-dimethylacetamide and the like; sulfoxides such as dimethylsulfoxide and the like; etc. These solvents may be used in admixture.

The base which is used, if desired, in this reaction includes, forexample, potassium acetate, sodium hydrogencarbonate, sodium carbonate,potassium carbonate, triethylamine and the like. The amount of the baseused is at least equal to the molar amount of, preferably 1 to 3 molesper mole of, the compound of the general formula [3] or its salt.

The metallic palladium used in this reaction includes, for example,palladium-activated carbon, palladium black and the like. The amount ofthe metallic palladium used is at least 0.00001 mole, preferably 0.001to 0.05 mole, per mole of the compound of the general formula [3] or itssalt.

The amount of the compound of the general formula [2] or its salt usedis at least equal to the molar amount of, preferably 1.0 to 1.5 molesper mole of, the compound of the general formula [3] or its salt.

This coupling reaction may be usually carried out in an atmosphere of aninert gas (for example, argon, nitrogen) at 50-170° C. for 1 minute to24 hours.

Incidentally, the compound of the general formula [3] or its salt can beproduced by, for example, the method described in WO097/29102.

Production Process IIA

(2.1) Process for Producing Compound of the General Formula [2a] or itsSalt

The compound of the general formula [2a] or its salt can be produced byreacting a compound of the general formula [4] or its salt with adialkoxyborane of the general formula [5a] or an alkoxydiborane of thegeneral formula [5b] in the presence or absence of a base using apalladium catalyst selected from metallic palladium, palladium salts andpalladium complexes.

The solvent which is used in this reaction may be any solvent as far asit does not adversely affect the reaction, and includes, for example,aromatic hydrocarbons such as benzene, toluene, xylene and the like;aliphatic hydrocarbons such as n-hexane, cyclohexane and the like;halogenated hydrocarbons such as methylene chloride, chloroform,dichloroethane and the like; ethers such as dioxane, tetrahydrofuran,anisole, diethylene glycol diethyl ether, dimethyl Cellosolve and thelike; esters such as ethyl acetate, butyl acetate and the like; ketonessuch as acetone, methyl ethyl ketone and the like; nitrites such asacetonitrile and the like; amides such as N,N-dimethylformamide,N,N-dimethylacetamide and the like; sulfoxides such as dimethylsulfoxideand the like; etc. These solvents may be used in admixture.

The base which is used, if desired, in this reaction includes, forexample, potassium acetate, potassium tert-butoxide,diisopropylethylamine, pyridine, 1,8-diazabicyclo[5.4.0]-7-undecene,tributylamine, triethylamine and the like. The amount of the base usedis at least equal to the molar amount of, preferably 1 to 3 moles permole of, the compound of the general formula [4] or its salt.

The metallic palladium used in this reaction includes, for example,metallic palladium such as palladium-activated carbon, palladium blackand the like; the palladium salt includes, for example, inorganicpalladium salts such as palladium chloride and the like and organicpalladium salts such as palladium acetate and the like; and thepalladium complex includes, for example, organic palladium complexessuch as tetrakis(triphenyl-phosphine)palladium(0),bis(triphenylphosphine)-palladium(II) chloride,1,1′-bis(diphenylphosphino)-ferrocenepalladium(II) chloride and thelike. The amount of a palladium catalyst selected from metallicpalladium, palladium salt and palladium complex used may be at least0.00001 mole, preferably 0.001 to 0.05 mole, per mole of the compound ofthe general formula [4] or its salt.

The dialkoxyborane which is used in this reaction includes, for example,4,4,5,5-tetramethyl-1,3,2-dioxaborolane, catecholborane and the like,and the alkoxydiborane includes, for example,4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-4′,4′,5′,5′-tetramethyl-1′,3′,2′-dioxaborolaneand the like.

The amount thereof used is at least equal to the molar amount of,preferably 1.0 to 1.5 moles per mole of, the compound of the generalformula [4] or its salt.

This reaction may be carried out in an atmosphere of an inert gas (forexample, argon, nitrogen) at 0-150° C., preferably 80-110° C., for 1-24hours.

(2.2) Process for Producing Compound of the General Formula [1] or itsSalt

The compound of the general formula [1] or its salt can be produced byadding the compound of the general formula [2a] or its salt produced inthe above (2.1) without isolation to the reaction mixture and, ifnecessary, additionally adding a palladium catalyst, adding thereto thecompound of the general formula [3] or its salt in the presence orabsence of a base in an atmosphere of an inert gas (for example, argon,nitrogen), and further subjecting them to reaction.

When the compounds of the general formulas [2], [2a], [3] and [4] ortheir salts in the above-mentioned production process have isomers (forexample, optical isomers, geometric isomers, tautomers and the like),these isomers can be used, and their solvates, hydrates and crystals ofvarious forms can be used.

Furthermore, the amino groups of the compounds of the general formulas[2], [2a], [3] and [4] or their salts can be previously protected with aconventional protecting group and the protecting group can be removed ina manner known per se after the reaction.

The thus produced compound of the general formula [1] or its salt can beisolated and purified in at least one conventional manner such asextraction, crystallization, column chromatography or the like.

Among the compounds of the general formula [1] produced by the processof this invention, there can be mentioned, as preferable compounds,compounds of the general formula [1] wherein R² is a substituted orunsubstituted cycloalkyl group; R³ is a hydrogen atom, a halogen atom oran alkyl group; R⁴ is a hydrogen atom or an alkyl group; R⁵ is ahydrogen atom or an alkyl group; and A is CH or C—R⁷ in which R⁷ is ahalogen atom, a halogen-substituted or unsubstituted lower alkyl orlower alkoxy group. As representative compounds, there are mentioned,for example, the following compounds:

1-cyclopropyl-7-(isoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

8-chloro-1-cyclopropyl-7-(isoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

1-cyclopropyl-8-fluoro-7-(isoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

1-cyclopropyl-7-(isoindolin-5-yl)-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

1-cyclopropyl-7-(isoindolin-5-yl)-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

1-cyclopropyl-8-difluoromethoxy-7-(isoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

1-cyclopropyl-7-(isoindolin-5-yl)-8-trifluoro-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

7-(7-chloroisoindolin-5-yl)-1-cyclopropyl-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

1-cyclopropyl-7-(7-fluoroisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

1-cyclopropyl-7-(7-fluoroisoindolin-5-yl)-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

1-cyclopropyl-7-(7-fluoroisoindolin-5-yl)-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

1-cyclopropyl-8-difluoromethoxy-7-(7-fluoroisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

1-cyclopropyl-7-(7-fluoroisoindolin-5-yl)-8-trifluoromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

1-cyclopropyl-8-methoxy-7-(7-methylisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

1-cyclopropyl-7-(2-methylisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

1-cyclopropyl-8-methyl-7-(2-methylisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

1-cyclopropyl-8-methoxy-7-(2-methylisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

1-cyclopropyl-8-difluoromethoxy-7-(2-methyl-isoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

1-cyclopropyl-7-(2-methylisoindolin-5-yl)-8-trifluoromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

(±)-1-cyclopropyl-7-(1-methylisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

(±)-1-cyclopropyl-8-methyl-7-(1-methylisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

(+)-1-cyclopropyl-8-methyl-7-(1-methylisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

(−)-1-cyclopropyl-8-methyl-7-(1-methylisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

(±)-1-cyclopropyl-8-methoxy-7-(1-methyl-isoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

(+)-1-cyclopropyl-8-methoxy-7-(1-methyl-isoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

(−)-1-cyclopropyl-8-methoxy-7-(1-methyl-isoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

(±)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-isoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

(+)-l-cyclopropyl-8-difluoromethoxy-7-(1-methylisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

(−)-l-cyclopropyl-8-difluoromethoxy-7-(1-methylisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

1-cyclopropyl-7-(4-fluoroisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

1-cyclopropyl-7-(4-fluoroisoindolin-5-yl)-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

1-cyclopropyl-7-(4-fluoroisoindolin-5-yl)-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

1-cyclopropyl-8-difluoromethoxy-7-(4-fluoro-isoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

1-cyclopropyl-7-(4-fluoroisoindolin-5-yl)-8-trifluoromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

1-cyclopropyl-7-(6-fluoroisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

1-cyclopropyl-7-(6-fluoroisoindolin-5-yl)-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

1-cyclopropyl-7-(6-fluoroisoindolin-5-yl)-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

1-cyclopropyl-8-difluoromethoxy-7-(6-fluoro-isoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

1-cyclopropyl-7-(6-fluoroisoindolin-5-yl)-8-trifluoromethyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

1-cyclopropyl-7-(4,7-difluoroisoindolin-5-yl)-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

1-cyclopropyl-7-(4,7-difluoroisoindolin-5-yl)-8-methyl-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

1-cyclopropyl-7-(4,7-difluoroisoindolin-5-yl)-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylicacid,

1-cyclopropyl-7-(4,7-difluoroisoindolin-5-yl)-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylicacid, and

1-cyclopropyl-7-(4,7-difluoroisoindolin-5-yl)-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylicacid.

Furthermore, among the compounds of the general formula [2a] produced bythe process of this invention, there can be mentioned, as preferablecompounds, compounds of the general formula [2a] wherein R³ is ahydrogen atom, a halogen atom or an alkyl group; R⁴ is a hydrogen atomor an alkyl group; R⁵ is a hydrogen atom or an alkyl group; and Z is1,1,2,2-tetramethylethylene, and as representative compounds, there arementioned, for example, the following compounds:

5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline,

7-chloro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline,

7-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline,

7-methyl-5-(4,4,5, 5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline,

2-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline,

1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline,

(±)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline,

(+)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline,

(−)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline,

4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline,

6-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline, and

4,7-difluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline.

II. Process for Producing 1-alkylisoindoline-5-boronic Acid Derivative

wherein R^(4a), R⁵, R⁸, R⁹ and X¹ have the same meanings as mentionedabove, R⁵a represents a substituted or unsubstituted alkyl, cycloalkyl,alkylsulfonyl, arylsulfonyl, acyl or aryl group, and R¹⁰ represents ahydrogen atom or a carboxyl-protecting group.

The compounds of the general formulas [2b], [4a], [6], [7], [8], [9] and[10] can also be used in the form of salts, and as the salts, there canbe mentioned usually known salts at basic groups such as amino group andthe like and at acidic groups such as hydroxyl group, carboxyl group andthe like. The salt at basic group includes, for example, salts withmineral acids such as hydrochloric acid, hydrobromic acid, sulfuric acidand the like; salts with organic carboxylic acids such as tartaric acid,formic acid, lactic acid, citric acid, trichloroacetic acid,trifluoroacetic acid and the like; and salts with sulfonic acids such asmethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,mesitylenesulfonic acid, naphthalenesulfonic acid and the like.Furthermore, the salt at acidic group includes, for example, salts withalkali metals such as sodium, potassium and the like; salts withalkaline earth metals such as calcium, magnesium and the like; saltswith ammonium; salts with nitrogen-containing organic bases such astrimethylamine, triethylamine, tributylamine, pyridine,N,N-dimethylaniline, N-methylpiperidine, N-methylmorpholine,diethylamine, dicyclohexylamine, procaine, dibenzylamine,N-benzyl-b-phenethylamine, 1-ephenamine, N,N′-dibenzylethylenediamineand the like; etc.

(1) Process for Producing Compound of the General Formula [9] or itsSalt

The compound of the general formula [9] or its salt can be produced byreacting a compound of the general formula [10] or its salt with carbondioxide, a halogenated formic acid ester or a carbonic acid ester in thepresence of a base.

The solvent which is used in this reaction may be any solvent as far asit does not adversely affect the reaction, and includes, for example,aliphatic hydrocarbons such as n-hexane, cyclohexane and the like;ethers such as diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran,dioxane and the like; etc. These solvents may be used in admixture.

The base which is used in this reaction includes, for example, alkylmetal or aryl metal reagents such as n-butyllithium, tert-butyllithium,phenyllithium, methyl-lithium and the like; and amide bases such aslithium diisopropylamide, lithium bistrimethylsilylamide and the like.

The halogenated formic acid ester includes, for example, methylchloroformate, ethyl chloroformate and the like.

The carbonic acid ester includes, for example, dimethyl carbonate,diethyl carbonate, diphenyl carbonate and the like.

The amounts of the base and carbon dioxide, halogenated formic acidester or carbonic acid ester used are at least 2 moles, preferably 2 to3 moles, per mole of the compound of the general formula [10] or itssalt.

This reaction may be usually carried out at −70 to 20° C., preferably−50 to 0° C., for 10 minutes to 24 hours.

The obtained compound of the general formula [9] or its salt may be usedas it is without isolation in the subsequent reaction.

(2) Process for Producing Compound of the General Formula [8] or itsSalt

The compound of the general formula [8] or its salt can be produced bysubjecting the compound of the general formula [9] or its salt tohalogenation reaction.

The solvent which is used in this reaction may be any solvent as far asit does not adversely affect the reaction, and includes, for example,carboxylic acids such as acetic acid and the like; halogenatedhydrocarbons such as carbon tetrachloride and the like; inorganic acidssuch as sulfuric acid, hydrochloric acid and the like; water; etc. Thesesolvents may be used in admixture.

The halogenating agent which is used in this reaction includes, forexample, halogens such as chlorine, bromine, iodine and the like;organic halogen compounds such as N-bromosuccinimide, halogenatedisocyanuric acids such as sodium N-bromoisocyanurate and the like; etc.

The amount of the halogenating agent used is at least equal to the molaramount of, preferably 1 to 1.5 moles per mole of, the compound of thegeneral formula [9] or its salt.

This reaction may be carried out at −10 to 100° C., preferably 0 to 30°C., for 10 minutes to 24 hours.

The obtained compound of the general formula [8] or its salt may be usedas it is without isolation in the subsequent reaction.

(3) Process for Producing Compound of the General Formula [4a] or itsSalt The compound of the general formula [4a] or its salt can beproduced by reducing the compound of the general formula [8] or its saltto produce a compound of the general formula [6] or its salt andthereafter subjecting the compound of the general formula [6] or itssalt to ring-closing reaction or alternatively by ring-closing thecompound [8] or its salt to produce a compound of the general formula[7] or its salt and thereafter subjecting the compound of the generalformula [7] or its salt to reduction reaction.

The solvent which is used in this reduction reaction may be any solventas far as it does not adversely affect the reaction, and includes, forexample, alcohols such as methanol, ethanol, isopropanol and the like;ethers such as tetrahydrofuran, dioxane, 1,2-dimethoxyethane, diethyleneglycol dimethyl ether and the like; nitriles such as acetonitrile andthe like; amides such as N,N-dimethylformamide and the like; sulfoxidessuch as dimethylsulfoxide and the like; water; etc. These solvents maybe used in admixture.

The reducing agent which is used in this reaction includes, for example,alkali metals such as lithium, sodium, potassium and the like; alkalineearth metals such as magnesium, calcium and the like; metals and theirsalts such as zinc, aluminum, chromium, titanium, iron, samarium,selenium, sodium hydrosulfite and the like; metal hydrides such asdiisobutylaluminum hydride, trialkylaluminum hydride, tin hydridecompound, hydrosilane and the like; borohydride complex compounds suchas sodium borohydride, lithium borohydride, potassium borohydride,calcium borohydride and the like; aluminum hydride complex compoundssuch as lithium aluminum hydride and the like, etc.; boranes;alkylboranes; and the like.

The amount of the reducing agent used in this reaction is varieddepending upon the kind of the reducing agent; however, at least 0.25mole is required and, for example, in the case of the boron hydridecomplex compound, the above amount is at least 0.25 mole, preferably0.25 to 2 moles, per mole of the compound of the general formula [8] or[7] or its salt.

This reaction may be carried out usually at −20 to 100° C., preferably 0to 50° C., for 10 minutes to 24 hours.

The solvent which is used in this ring-closing reaction may be anysolvent as far as it does not adversely affect the reaction, andincludes, for example, ethers such as tetrahydrofuran, dioxane,1,2-dimethoxyethane, diethylene glycol dimethyl ether and the like;nitrites such as acetonitrile and the like, amides such asN,N-dimethylformamide and the like; sulfoxides such as dimethylsulfoxideand the like; aromatic hydrocarbons such as benzene, toluene, xylene andthe like; water; etc. These solvents may be used in admixture.

When the compound of the general formula [8] or its salt is subjected toring-closing reaction to produce a compound of the general formula [7]or its salt, or when the compound of the general formula [6] or its saltis subjected to activation of its hydroxyl group and thereafter toring-closing reaction to produce a compound of the general formula [4a]or its salt, the base which is if desired used includes, for example,sodium hydroxide, potassium hydroxide, sodium tert-butoxide, potassiumtert-butoxide, sodium hydride and the like, and the amount of the baseused is at least equal to the molar amount of, preferably 1 to 1.5 molesper mole of, the compound of the general formula [8] or [6] or its salt.

Furthermore, as the catalyst which is if desired used, a usually knownphase transfer catalyst of quaternary ammonium salt is used; however,preferable are tetra-n-butylammonium bromide, tetra-n-butylammoniumhydrogen-sulfate and the like. The amount of the catalyst used is 0.01to 0.2 mole per mole of the compound of the formula [8] or [6] or itssalt.

This reaction may be carried out at usually 0 to 100° C., preferably 0to 30° C., for 10 minutes to 24 hours.

The obtained compound of the general formula [4a] or its salt may beused as it is without isolation in the subsequent reaction.

(4) Process for Producing Compound of the General Formula [2b] or itsSalt

The compound of the general formula [2b] or its salt can be produced bysubjecting the compound of the general formula [4a] or its salt toborodation.

Specifically, according to, for example, the method described in JikkenKagaku Koza, 4th edition, Vol. 24, pages 61-90 (1992), it can beobtained by subjecting a compound of the formula [4b] or its salt tolithiation or Grignard reaction and thereafter to reaction with atrialkyl borate.

The solvent which is used in this reaction may be any solvent as far asit does not adversely affect the reaction, and includes, for example,aliphatic hydrocarbons such as n-hexane, cyclohexane and the like;ethers such as diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran,dioxane and the like; etc. These solvents may be used in admixture.

The lithiating agent which is used in this reaction includes, forexample, alkyl metal reagents such as n-butyllithium, tert-butyllithium,phenyllithium, methyllithium and the like; and amide bases such aslithium diisopropylamide, lithium bistrimethylsilylamide and the like.Moreover, the Grignard reagent can be obtained by reacting metallicmagnesium with the compound represented by the general formula [4a] orits salt.

The trialkyl borate which is used in this reaction includes, forexample, trimethyl borate, triethyl borate, triisopropyl borate,tributyl borate and the like.

The amount of the lithionizing agent, metallic magnesium or trialkylborate used is at least equal to the molar amount of, preferably 1 to 2moles per mole of, the compound of the general formula [4a] or its salt.

This reaction may be carried out usually at −70 to 50° C., preferably−60 to 0° C., for 10 minutes to 24 hours.

The obtained compound of the general formula [2b] or its salt may beused as it is without isolation in the subsequent reaction.

The thus obtained compound of the general formula [2b] or its salt canbe subjected to, for example, protection or deprotection to be convertedto the other compound of the general formula [2b] or its salt.

When the compounds of the general formula [2b], [4a], [6], [7], [8], [9]and [10] or their salts in the above-mentioned production process haveisomers (for example, optical isomers, geometrical isomers, tautomersand the like), these isomers can be used, and their solvates, hydratesand crystals of various forms can also be used.

When the compounds of the general formulas [4a], [6], [7], [8], [9] and[10] or their salts have an amino group, a hydroxyl group or a carboxylgroup, it is also possible to previously protect these groups with aconventional protecting group and remove the protecting group after thereaction in a manner known per se.

Next, the process for producing a compound of the general formula [1a]or its salt using the compound of the general formula [2b] or its saltas the starting material is explained.

Production Process IIB

wherein R¹, R², R^(4a), R⁵, R⁶, R⁸, R⁹, X³ and A have the same meaningsas mentioned above.

The compound of the general formula [1a] or its salt can be obtained bysubjecting a compound of the general formula [3b] or its salt and thecompound of the general formula [2b] or its salt to coupling reactionusing a palladium complex catalyst in the presence or absence of a base.

The solvent which is used in this reaction may be any solvent as far asit does not adversely affect the reaction, and includes, for example,water; alcohols such as methanol, ethanol, propanol and the like;aromatic hydrocarbons such as benzene, toluene, xylene and the like;halogenated hydrocarbons such as methylene chloride, chloroform,dichloroethane and the like; ethers such as dioxane, tetrahydrofuran,anisole, diethylene glycol diethyl ether, dimethyl Cellosolve and thelike; esters such as ethyl acetate, butyl acetate and the like; ketonessuch as acetone, methyl ethyl ketone and the like; nitrites such asacetonitrile and the like; amides such as N,N-dimethylformamide,N,N-dimethylacetamide and the like; sulfoxides such as dimethylsulfoxideand the like; etc. These solvents may be used in admixture.

The base which is used, if desired, in this reaction includes, forexample, sodium hydrogencarbonate, sodium carbonate, potassiumcarbonate, triethylamine and the like.

The palladium complex catalyst which is used in this reaction includes,for example, inorganic palladium salts such as palladium chloride andthe like; organic palladium salts such as palladium acetate and thelike; and organic palladium complexes such astetrakis(triphenyl-phosphine)palladium(0),bis(triphenylphosphine)-palladium(II) chloride,1,1′-bis(diphenylphosphino)-ferrocenepalladium(II) chloride and thelike.

The amount of the compound of the general formula [2b] or its salt usedis at least equal to the molar amount of, preferably 1.0 to 1.5 molesper mole of, the compound of the general formula [3b] or its salt.

This coupling reaction may be carried out usually in an atmosphere of aninert gas (for example, argon, nitrogen) at 50 to 170° C. for 1 minuteto 24 hours.

The salt of the compound of the general formula [1a] includes, forexample, the same salts as those mentioned as to the compounds of thegeneral formulas [2b], [4a], [6], [7], [8], [9] and [10].

The compound of the general formula [3b] or its salt can be produced by,for example, the method described in WO097/29102. III. Process forproducing 1-alkyl-5-halogenoiso-indoline derivative

Production Process IIIA

wherein R^(4a), R⁵ and X¹ have the same meanings as mentioned above;R^(5b), R^(5c) and R^(5d) may be the same or different and eachrepresents an alkyl group; and Y represents a leaving group.

The leaving group for Y includes, for example, halogen atoms; loweralkylsulfonyloxy groups such as methylsulfonyloxy, ethylsulfonyloxy,isopropylsulfonyloxy and the like; arylsulfonyloxy groups such asphenylsulfonyloxy, naphthylsulfonyloxy and the like; etc.

Furthermore, as the alkyl groups for R^(5b), R^(5c) and R^(5d), loweralkyl groups such as methyl group and the like are preferable.

The compounds of the general formulas [12] and [11] can also beconverted to their salts, and as the salts, there can be mentionedusually known salts at basic groups such as amino group and the like. Asthe salts at the basic groups, there can be mentioned, for example,salts with mineral acids such as hydrochloric acid, hydrobromic acid,sulfuric acid and the like; salts with organic carboxylic acids such astartaric acid, formic acid, lactic acid, citric acid, trichloroaceticacid, trifluoroacetic acid and the like; salts with sulfonic acids suchas methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid,mesitylenesulfonic acid, naphthalenesulfonic acid and the like; etc.

Furthermore, the salts of the compounds of the general formulas [6] and[4a] in the present production process include the same salts asmentioned as to Production Process IIA.

(1) Process for Producing Compound of the General Formula [6] or itsSalt

The compound of the general formula [6] or its salt can be produced byreacting the compound of the general formula [12] or its salt with aformaldehyde or its derivative in the presence of an aryllithium.

The solvent which is used in this reaction may be any solvent as far asit does not adversely affect the reaction, and includes, for example,aliphatic hydrocarbons such as n-hexane, cyclohexane and the like;ethers such as diethyl ether, n-dibutyl ether, 1,2-dimethoxyethane,tetrahydrofuran, dioxane and the like. These solvents may be used inadmixture.

The aryllithium which is used in this invention includes, for example,phenyllithium, biphenyllithium, naphthyllithium and the like.

The formaldehyde or its derivative includes, for example, formaldehyde,paraformaldehyde, trioxane and the like.

The amounts of the aryllithium and the formaldehyde or its derivativeused are at least 2 moles, preferably 2 to 5 moles, per mole of thecompound of the general formula [12] or its salt.

This reaction may be carried out at usually −70 to 50° C., preferably−30 to 30° C., for 10 minutes to 24 hours.

The obtained compound of the general formula [6] or its salt may be usedas it is without isolation in the subsequent reaction.

Moreover, the amino-protecting group may be subjected to eliminationreaction after the reaction and a new amino-protecting group may beintroduced.

(2) Process for Producing Compound of the General Formula [11] or itsSalt

The compound of the general formula [11] or its salt can be produced byreacting the compound of the general formula [6] or its salt with ahalogenating agent, a sulfonylating agent or the like in the presence orabsence of a base.

The solvent which is used in this reaction may be any solvent as far asit does not adversely affect the reaction, and includes, for example,aliphatic hydrocarbons such as n-hexane, cyclohexane and the like;halogenated hydrocarbons such as methylene chloride, chloroform and thelike; ethers such as tetrahydrofuran, 1,2-dimethoxyethane, dioxane andthe like; aromatic hydrocarbons such as benzene, toluene, xylene and thelike; sulfoxides such as dimethylsulfoxide and the like; amides such asN,N-dimethylformamide and the like; esters such as ethyl acetate and thelike; nitrites such as acetonitrile and the like; etc. These solventsmay be used in admixture.

Moreover, the base which is used, if necessary, includes, for example,organic and inorganic bases such as triethylamine,diisopropylethylamine, 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU),pyridine, potassium tert-butoxide, sodium carbonate, potassiumcarbonate, sodium hydride and the like.

The halogenating agent includes, for example, phosphorus oxychloride,phosphorous oxybromide, phosphorus trichloride, phosphoruspentachloride, thionyl chloride and the like.

The sulfonylating agent includes, for example, methanesulfonyl chloride,p-toluenesulfonyl chloride and the like.

The amount of the halogenating agent or sulfonylating agent used and theamount of the base which is used, if necessary, are at least equal tothe molar amount of, preferably 1 to 5 moles per mole of, the compoundof the general formula [6] or its salt.

This reaction may be carried out at usually −10 to 100° C., preferably 0to 50° C., for 10 minutes to 24 hours.

The salt of the obtained compound of the general formula [11] or itssalt may be used as it is without isolation in the subsequent reaction.

(3) Process for Producing Compound of the General Formula [4a] or itsSalt

The compound of the general formula [4a] or its salt can be produced bysubjecting the compound of the general formula [11] or its salt toring-closing reaction in the presence of a base and in the presence orabsence of a catalyst.

The solvent which is used in this reaction may be any solvent as far asit does not adversely affect the reaction, and includes, for example,aliphatic hydrocarbons such as n-hexane, cyclohexane and the like;aromatic hydrocarbons such as benzene, toluene and the like; ethers suchas tetrahydrofuran, dioxane, diethylene glycol dimethyl ether,di-n-butyl ether and the like; halogenated hydrocarbons such asmethylene chloride, chloroform and the like; nitrites such asacetonitrile and the like; amides such as N,N-dimethylformamide and thelike; sulfoxides such as dimethylsulfoxide and the like; water; etc.These solvents may be used in admixture.

The base which is used in this reaction includes, for example, sodiumhydroxide, potassium hydroxide, potassium tert-butoxide, sodium hydrideand the like.

As the catalyst which is used, if necessary, there are used phasetransfer catalysts of usually known quaternary ammonium salts. However,preferably, there are mentioned tetra-n-butylammonium bromide,tetra-n-butyl-ammonium hydrogensulfate and the like.

The amount of the base used is at least equal to the molar amount of,preferably 1 to 10 moles per mole of, the compound of the generalformula [11] or its salt, and the amount of the catalyst which is used,if necessary, is 0.01 to 0.2 mole per mole of the compound of thegeneral formula [11] or its salt.

This reaction may be carried out at usually 0 to 100° C., preferably 0to 40° C., for 10 minutes to 24 hours.

The compound of the general formula [4a] or its salt may be used as itis without isolation in the subsequent reaction.

Furthermore, if necessary, after the removal of the protecting group ofR⁵, a new protecting group may be introduced into the compound of thegeneral formula [4a] or its salt taking the subsequent production routeinto consideration.

When the compounds of the general formulas [4a], [6], [11] and [12] ortheir salts in the above-mentioned production process have isomers (forexample, optical isomers, geometrical isomers, tautomers and the like),these isomers can be used. Also, solvates, hydrates and crystals ofvarious forms can be used.

Moreover, when the compounds of the general formulas [4a], [6], [11] and[12] or their salts have an amino group, a hydroxyl group or a carboxylgroup, it is possible to previously protect these groups with aconventional protecting group and remove the protecting group after thereaction in a manner known per se.

Next, a process for producing a compound of the general formula [1a] orits salt using the compound of the general formula [4a] or its salt asthe starting material is explained.

Production Process IIIB

wherein R¹, R², R^(4a), R⁵, R⁶, R⁸, R⁹, A, X¹ and X² have the samemeanings as mentioned above.

(1) Process for Producing Compound of the General Formula [2b] or itsSalt

The compound of the general formula [2b] or its salt can be produced bysubjecting the compound of the general formula [4a] or its salt toborodation.

Specifically, it can be obtained by subjecting the compound of thegeneral formula [4a] or its salt to lithiation or Grignard reactionaccording to, for example, the method described in Jikken Kagaku Koza,4th edition, Vol. 24, pages 61-90 (1992), and thereafter to reactionwith trialkyl borate.

The solvent which is used in this reaction may be any solvent as far asit does not adversely affect the reaction, and includes, for example,aliphatic hydrocarbons such as n-hexane, cyclohexane and the like;ethers such as diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran,dioxane and the like; etc. These solvents may be used in admixture.

The lithiating agent which is used in this reaction includes, forexample, alkyl metal or aryl metal reagents such as n-butyllithium,tert-butyllithium, phenyllithium, methyllithium and the like; and amidebases such as lithium diisopropylamide, lithium bistrimethylsilylamideand the like. Moreover, the Grignard reagent can be obtained by reactingmetallic magnesium with the compound represented by the formula [4a] orits salt.

The trialkyl borate which is used in this reaction includes, forexample, trimethyl borate, triethyl borate, triisopropyl borate,tributyl borate and the like.

The amounts of the lithiating agent, metallic magnesium and trialkylborate used are at least equal to the molar amount of, preferably 1 to 2moles per mole of, the compound of the general formula [4a] or its salt.

This reaction may be carried out at usually −70 to 50° C., preferably−60 to 0° C., for 10 minutes to 24 hours.

The obtained compound of the general formula [2b] or its salt may beused as it is without isolation in the subsequent reaction.

(2) Process for Producing Compound of the General Formula [1a] or itsSalt

The compound of the general formula [1a] or its salt can be obtained bysubjecting the compound of the general formula [2b] or its salt and thecompound of the general formula [3] or its salt to coupling reactionusing a palladium catalyst in the presence or absence of a base.

The solvent which is used in this reaction is not particularly limitedas far as it does not adversely affect the reaction, and includes, forexample, water; alcohols such as methanol, ethanol, propanol and thelike; aromatic hydrocarbons such as benzene, toluene, xylene and thelike; halogenated hydrocarbons such as methylene chloride, chloroform,dichloroethane and the like; ethers such as dioxane, tetrahydrofuran,anisole, diethylene glycol dimethyl ether, diethylene glycol diethylether, ethylene glycol dimethyl ether and the like; esters such as ethylacetate, butyl acetate and the like; ketones such as acetone, methylethyl ketone and the like; nitrites such as acetonitrile and the like;amides such as N,N-dimethyl-formamide, N,N-dimethylacetamide and thelike; sulfoxides such as dimethylsulfoxide and the like; etc. Thesesolvents may be used in admixture.

The base which is used, if desired, in this reaction includes, forexample, sodium hydrogencarbonate, sodium carbonate, potassiumcarbonate, triethylamine and the like, and the amount of the base usedis at least equal to the molar amount of, preferably 2 to 5 moles permole of, the compound of the general formula [3] or its salt.

Moreover, the palladium catalyst which is used in this reactionincludes, for example, metallic palladium such as palladium-activatedcarbon, palladium black and the like; inorganic palladium salts such aspalladium chloride and the like; organic palladium salts such aspalladium acetate and the like; and organic palladium complexes such astetrakis(triphenylphosphine)palladium(0),bis(triphenyl-phosphine)palladium(II) chloride,1,1′-bis(diphenyl-phosphino)ferrocenepalladium(II) chloride and thelike.

The amount of the palladium catalyst used is at least 0.00001 mole,preferably 0.001 to 0.05 mole, per mole of the compound of the generalformula [3] or its salt.

The amount of the compound of the general formula [2b] or its salt usedis at least equal to the molar amount of, preferably 1.0 to 1.5 molesper mole of, the compound of the general formula [3] or its salt.

This coupling reaction may be carried out usually in an atmosphere of aninert gas (for example, argon, nitrogen) at 50 to 170° C. for 1 minuteto 24 hours.

The salts of the compounds of the general formulas [1a], [2b] and [3] inProduction Process IIIB include the same salts as explained above.

The compound of the general formula [3] or its salt can be produced by,for example, the method described in WO097/29102.

IV. Process for Producing 7-bromoquinolonecarboxylic Acid Derivative

Production Process IVA

wherein R¹, R^(2a) and R^(7a) have the same meanings as mentioned above;R^(1a) represents a carboxyl-protecting group; and X represents ahalogen atom.

As the compounds of the general formulas [3a] and [13] to [19] can beconverted to their salts, and as these salts, there can be mentionedusually known salts at basic groups such as amino group and the like andat acidic groups such as hydroxyl group, carboxyl group and the like.The salts at the basic groups include, for example, salts with mineralacids such as hydrochloric acid, hydrobromic acid, sulfuric acid and thelike; salts with organic carboxylic acids such as tartaric acid, formicacid, lactic acid, citric acid, trichloroacetic acid, trifluoroaceticacid and the like; and salts with sulfonic acids such as methanesulfonicacid, benzenesulfonic acid, p-toluene-sulfonic acid, mesitylenesulfonicacid, naphthalenesulfonic acid and the like. Also, the salts at theacidic groups include, for example, salts with alkali metals such assodium, potassium and the like; salts with alkaline earth metals such ascalcium, magnesium and the like; salts with ammonium; salts withnitrogen-containing organic bases such as trimethylamine, triethylamine,tributylamine, pyridine, N,N-dimethylaniline, N-methylpiperidine,N-methyl-morpholine, diethylamine, dicyclohexylamine, procaine,dibenzylamine, N-benzyl-b-phenethylamine, 1-ephenamine,N,N′-dibenzylethylenediamine and the like; etc.

(1) Process for Producing Compound of the General Formula [15] or itsSalt

The compound of the general formula [15] or its salt can be produced byreacting a compound of the general formula [13] or its salt with acompound of the general formula [14] in the presence or absence of abase.

The solvent which is used in this reaction may be any solvent as far asit does not adversely affect the reaction, and includes, for example,aliphatic hydrocarbons such as n-hexane, cyclohexane and the like;aromatic hydrocarbons such as benzene, toluene, xylene and the like;ethers such as diethyl ether, 1,2-dimethoxyethane, tetrahydrofuran,dioxane and the like; halogenated hydrocarbons such as methylenechloride, chloroform, dichloroethane and the like; amides such asN,N-dimethylformamide, N,N-dimethylacetamide and the like; nitrites suchas acetonitrile and the like; sulfoxides such as dimethylsulfoxide andthe like; water; etc. These solvents may be used in admixture. Moreover,when water is used as the solvent, the use of a usually known phasetransfer catalyst is effective.

The phase transfer catalyst used includes, for example, quaternaryammonium salts such as tetramethyl-ammonium bromide, tetrabutylammoniumbromide, tetrabutyl-ammonium chloride, tetrabutylammoniumhydrogensulfate and the like. When the phase transfer catalyst is used,the amount thereof used is at least 0.1 mole, preferably 0.3 to 1.0mole, per mole of the compound of the general formula [13] or its salt.

As the base which is used, if desired, there are mentioned sodiumhydroxide, potassium hydroxide, sodium hydrogencarbonate, potassiumcarbonate, potassium tertbutoxide, sodium hydride and the like.

The amounts of the base and the compound of the general formula [14]used is each at least equal to the molar amount of, preferably 1 to 10moles per mole of, the compound of the general formula [13] or its salt.

This reaction may be carried out usually at 0 to 180° C. for 5 minutesto 30 hours.

The obtained compound of the general formula [15] or its salt may beused as it is without isolation in the subsequent reaction.

(2) Process for Producing Compound of the General Formula [16] or itsSalt

The compound of the general formula [16] or its salt can be obtained bysubjecting the compound of the general formula [15] or its salt toconventional elimination reaction of carboxyl-protecting group.

(3) Process for Producing Compound of the General Formula [17] or itsSalt

The compound of the general formula [17] or its salt can be obtained bysubjecting the compound of the general formula [16] or its salt toketoesterification reaction usually known in this field.

(3-a) The compound of the general formula [17] or its salt can beobtained by activating the carboxyl group of the compound of the generalformula [16] or its salt according to the method described in Angew.Chem. Int. Ed. Engl., Vol. 18, page 72 (1979), for example, byconverting the carboxyl group to an active acid amide form or the likeusing N,N′-carbonyldiimidazole, and thereafter reacting the activatedspecies with a magnesium salt of a malonic acid monoester.

The solvent which is used in this reaction is not particularly limitedas far as it does not adversely affect the reaction, and includes, forexample, aromatic hydrocarbons such as benzene, toluene, xylene and thelike; ethers such as dioxane, tetrahydrofuran, diethyl ether and thelike; halogenated hydrocarbons such as methylene chloride, chloroform,dichloroethane and the like; and amides such as N,N-dimethylformamide,N,N-dimethylacetamide and the like. These solvents may be used inadmixture.

The amount of the magnesium salt of a malonic acid monoester used is atleast equal to the molar amount of, preferably 1 to 2 moles per mole of,the compound of the general formula [16] or its salt.

This reaction may be carried out at usually 0 to 100° C., preferably 10to 80° C., for 5 minutes to 30 hours.

(3-b) Alternatively, the compound of the general formula [17] or itssalt can be obtained by, for example, converting the carboxyl group ofthe compound of the general formula [16] or its salt to an acid halideusing a halogenating agent such as thionyl chloride or the like,thereafter reacting the acid halide with a salt of a malonic aciddiester with a metal such as sodium, ethoxymagnesium or the like, andthen subjecting the reaction product to partial removal of thecarboxyl-protecting group and decarbonization reaction usingp-toluenesulfonic acid or trifluoroacetic acid in a water-containingsolvent.

The solvent which is used in the reaction of the acid halide with themetal salt of a malonic acid diester is not particularly limited as faras it does not adversely affect the reaction, and specifically includesthe same solvents as in (3-a) above.

The amount of the metal salt of a malonic acid diester used is at leastequal to the molar amount of, preferably 1 to 3 moles per mole of, thecompound of the general formula [16] or its salt.

This reaction may be carried out usually at −50 to 100° C. for 5 minutesto 30 hours.

(4) Process for Producing Compound of the General Formula [19] or itsSalt

(4-a) The compound of the general formula [19] or its salt can beobtained by reacting the compound of the general formula [17] or itssalt with an orthoester such as methyl orthoformate, ethyl orthoformateor the like in acetic anhydride and thereafter reacting the reactionproduct with a compound of the general formula [18] or its salt.

The solvent which is used in this reaction is not particularly limitedas far as it does not adversely affect the reaction, and include, forexample, aromatic hydrocarbons such as benzene, toluene, xylene and thelike; ethers such as dioxane, tetrahydrofuran, anisole, diethyleneglycol diethyl ether, methyl Cellosolve and the like; alcohols such asmethanol, ethanol, propanol and the like; halogenated hydrocarbons suchas methylene chloride, chloroform, dichloroethane and the like; amidessuch as N,N-dimethylformamide, N,N-dimethylacetamide and the like;sulfoxides such as dimethyl sulfoxide and the like; etc. These solventsmay be used in admixture.

The amount of the orthoester used is at least equal to the molar amountof, preferably 1 to 10 moles per mole of, the compound of the generalformula [17] or its salt. These reactions may be carried out at usually0 to 150° C., preferably 50 to 150° C., for 20 minutes to 50 hours.

In order to subsequently react the compound of the general formula [18]or its salt, it is sufficient to use this compound of the generalformula [18] or its salt in an amount at least equal to the molar amountof the compound of the general formula [17] or its salt and it issufficient to carry out the reaction at usually 0 to 100° C., preferably10 to 60° C., for 20 minutes to 30 hours.

(4-b) Alternatively, the compound of the general formula [19] or itssalt can also be derived by reacting the compound of the general formula[17] or its salt with an acetal such as N,N-dimethylformamide dimethylacetal, N,N-dimethylformamide diethylacetal or the like in the presenceor absence of an acid anhydride such as acetic anhydride or the like andthereafter reacting the reaction product with the compound of thegeneral formula [18] or its salt.

When the acid anhydride is used, the amount thereof used is at leastequal to the molar amount of, preferably 1 to 5 moles per mole of, thecompound of the general formula [17] or its salt.

The solvent which is used in this reaction is not particularly limitedas far as it does not adversely affect the reaction, and specificallyincludes the same solvents as in (4-a) above.

The amount of the acetal used is at least equal to the molar amount of,preferably about 1 to 5 moles per mole of, the compound of the generalformula [17] or its salt.

These reactions may be carried out at usually 0 to 100° C., preferably20 to 85° C., for 20 minutes to 50 hours.

In order to subsequently react the compound of the general formula [18]or its salt, it is sufficient to use this compound of the generalformula [18] or its salt in an amount at least equal to the molar amountof the compound of the general formula [17] or its salt and it issufficient to carry out the reaction at usually 0 to 100° C., preferably10 to 60° C. for 20 minutes to 30 hours.

(5) Process for Producing Compound of the General Formula [3a] or itsSalt

The compound of the general formula [3a] or its salt can be obtained bysubjecting a compound of the general formula [19] or its salt toring-closing reaction in the presence or absence of a fluoride salt or abase.

The solvent which is used in this reaction is not particularly limitedas far as it does not adversely affect the reaction, and includes, forexample, amides such as N,N-dimethylformamide, N,N-dimethylacetamide andthe like; ethers such as dioxane, anisole, diethylene glycol dimethylether, dimethyl Cellosolve and the like; sulfoxides such as dimethylsulfoxide and the like; water; etc. These solvents may be used inadmixture.

The fluoride salt which is used, if desired, in this reaction includes,for example, sodium fluoride, potassium fluoride and the like.

The base which is used, if desired, in this reaction includes, forexample, sodium hydroxide, potassium hydroxide, sodiumhydrogencarbonate, potassium carbonate, potassium tert-butoxide, sodiumhydride and the like.

The amounts of the fluoride salt and base used is each at least equal tothe molar amount of, preferably 1.0 to 3.0 moles per mole of, thecompound of the general formula [19] or its salt. This reaction may becarried out usually at 0 to 180° C. for 5 minutes to 30 hours.

The obtained compound of the general formula [3a] or its salt may beused as it is without isolation in the subsequent reaction.

The thus obtained compound of the general formula [3a] or its salt canbe converted to the other compounds of the general formula [3a] or theirsalts by subjecting the former to protection reaction and/ordeprotection reaction.

When the salts of the compounds of the general formulas [3a] and [13] to[19] or their salts in the above-mentioned production process haveisomers (for example, optical isomers, geometrical isomers, tautomersand the like), these isomers can be used, and solvates, hydrates andcrystals of various forms can also be used.

Furthermore, when the compounds of the general formulas [3a] and [13] to[19] or their salts have an amino group, a hydroxyl group or a carboxylgroup, it is possible to previously protect these groups with aconventional protecting group and remove the protecting group after thereaction in a manner known per se.

Next, a process for producing a compound of the general formula [1b] orits salt using the compound of the general formula [3a] or its salt asthe starting material is explained.

Production Process IVB

wherein R¹, R^(1b), R^(2a), R³, R⁴, R⁵, R^(7a), R⁸ and R⁹ have the samemeanings as mentioned above.

The compound of the general formula [1b] or its salt can be produced bysubjecting the compound of the general formula [2] or its salt and thecompound of the general formula [3a] or its salt to coupling reactionusing a palladium catalyst in the presence or absence of a base.

The solvent which is used in this reaction is not particularly limitedas far as it does not adversely affect the reaction, and includes, forexample, water; alcohols such as methanol, ethanol, propanol and thelike; aromatic hydrocarbons such as benzene, toluene, xylene and thelike; halogenated hydrocarbons such as methylene chloride, chloroform,dichloroethane and the like; ethers such as dioxane, tetrahydrofuran,anisole, diethylene glycol diethyl ether, dimethyl Cellosolve and thelike; esters such as ethyl acetate, butyl acetate and the like; ketonessuch as acetone, methyl ethyl ketone and the like; nitrites such asacetonitrile and the like; amides such as N,N-dimethylformamide,N,N-dimethylacetamide and the like; sulfoxides such as dimethylsulfoxide and the like; etc. These solvents may be used in admixture.

The base which is used, if desired, in this reaction includes, forexample, sodium hydrogencarbonate, sodium carbonate, potassiumcarbonate, triethylamine and the like.

The palladium catalyst which is used in this reaction includes, forexample, metallic palladiums such as palladium-activated carbon,palladium black and the like; inorganic palladium salts such aspalladium chloride and the like; organic palladium salts such aspalladium acetate and the like; and organic palladium complexes such astetrakis(triphenylphosphine)palladium(0),bis(triphenylphosphine)palladium(II) chloride,1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride and the like.

The amount of the palladium catalyst used is at least 0.01% by mole,preferably 0.1 to 1.0% by mole, based on the amount of the compound ofthe general formula [3a] or its salt.

The amount of the compound of the general formula [2] or its salt usedis at least equal to the molar amount of, preferably 1.0 to 1.5 molesper mole of, the compound of the general formula [3a] or its salt.

This coupling reaction may be carried out usually in an atmosphere of aninert gas (for example, argon, nitrogen) at 50 to 170° C. for 1 minuteto 24 hours.

The salts of the compound of the general formula [1b] include the samesalts as the above-mentioned salts of the compounds of the generalformulas [3a] and [13] to [19].

The compound of the general formula [2] or its salt can be produced by,for example, the method described in WO097/29102 and the aboveProduction Processes IB and IIA.

The salts of the compound of the general formula [2] include the samesalts as the above-mentioned salts of the compounds of the generalformulas [3a] and [13] to [19].

V. Salt of 7-isoindoline-3-quinolinecarboxylic Acid, Hydrate Thereof andComposition Comprising the Same as Active Ingredient

In order to produce(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid (T-3811) methanesulfonate, it is sufficient to produce the same bya usually known process for producing a salt of a compound.Specifically, T-3811 methanesulfonate can be obtained by suspending ordissolving T-3811 in, for example, an alcohol such as methanol, ethanolor the like; N,N-dimethyl-formamide; a methanol-ether mixed solvent; orthe like, adding methanesulfonic acid to the resulting suspension orsolution to react with T-3811.

Moreover, T-3811 methanesulfonate can also be produced by dehydratingT-3811 methanesulfonate monohydrate in a solvent, for example, analcohol such as methanol, ethanol or the like; N,N-dimethylformamide; amethanol-ether mixed solvent; or the like.

In order to produce T-3811 methanesulfonate monohydrate, it issufficient to produce the same by a usually known method for producing ahydrate of salt of a compound. Specifically, T-3811 methanesulfonatemonohydrate can be produced by, for example, suspending or dissolvingT-3811 in a water-containing alcohol such as water-containing ethanol,water-containing isopropanol or the like; water-containing acetonitrile;water-containing acetone; water-containing tetrahydrofuran;water-containing acetic acid; water-containing N,N-dimethylformamide;water; or the like, adding methanesulfonic acid to the resultingsuspension or solution to react with T-3811.

When T-3811 methanesulfonate or its monohydrate is used as an activeingredient to prepare a composition thereof with an inactive ingredient,it is preferable to prepare a preparation composition in which theinactive ingredient is a carrier acceptable as preparation.

The carrier acceptable as preparation which is used in this inventionincludes specifically excipients such as lactose, corn starch,crystalline cellulose, mannitol, erythritol, sucrose and the like;disintegrators such as sodium carboxymethyl starch, calcium carmellose,sodium croscarmellose, hydroxypropyl cellulose of a low substitutiondegree, crospovidone and the like; binders such as hydroxypropylcellulose, povidone, methyl cellulose and the like; lubricants such asmagnesium stearate, calcium stearate, talc, light anhydrous silicic acidand the like; coating agents such as hydroxypropylmethyl cellulose,ethyl cellulose, polyvinyl alcohol, methacrylic acid copolymer,hydroxypropylmethyl cellulose acetate succinate and the like;plasticizers such as macrogol, glycerine triacetate, triethyl citrateand the like; coloring agents such as iron sesquioxide, yellow ironsesquioxide, food yellow No. 5, titanium oxide and the like; sweeteningagents such as sodium saccharate, aspartame, hydrogenated maltose starchand the like; viscosity improvers such as gelatine, sodium alginate andthe like; tonicity agents such as mannitol, glucose, xylitol and thelike; pH-adjusting agents such as methanesulfonic acid, sodium lactatesolution and the like; solvents such as water for injection and thelike; surface active agents such as polysorbate 80, sorbitan aliphaticacid ester, macrogol 400 and the like; ointment bases such as whitevaseline, polyethylene glycol, propylene glycol, cetanol and the like;etc.

Furthermore, the amount of the T-3811 methanesulfonate or itsmonohydrate contained in the composition is usually 0.05 to 70% byweight, preferably 0.5 to 20% by weight, based on the weight of thecomposition.

The composition of this invention can be prepared in various dosageforms, for example, internal solid and liquid dosage forms such astablet, capsule, granule, pilule, grain, powder, syrup and the like;solutions such as injection, eye drop and the like; hemi-solid dosageforms such as ointment, cream, gel, jelly and the like.

The dosage regimen, dose and number of administrations of thecomposition of this invention can be appropriately selected dependingupon the symptom of patient, and it is usually sufficient to administerthe composition in a proportion of 0.1 to 100 mg/kg per day per adult interms of T-3811 in one to several portions.

Next, the solubility of various salts of T-3811 is explained.

[Test Method]

The solubility of each salt of T-3811 was determined by the followingmethod:

To about 50 mg of each salt of T-3811 is added 2 ml of distilled waterand they are stirred and mixed. This sample solution is exposed toultrasonic wave irradiation 5 (SOLID STATE 1,200, Cho-onpa Kogyo) incold water for 3 hours and then filtered through a filter with a poresize of 0.45-μm (MILLEX-HV13, MILLIPORE). The T-3811 content in thisfiltrate is determined by a liquid chromatography.

The results obtained are shown in Table 1.

TABLE 1 Solubility Salt of T-3811 pH (μg/ml) Methanesulfonate 3.66 16510Phosphate 3.29 8520 L-lactate 4.40 1980 Sodium salt 10.11 2340 Citrate3.90 420 Acetate 4.22 6230 Hydrochloride 3.99 5450 Magnesium salt 7.5860 Sulfate 3.46 1170

BEST MODE FOR CARRYING OUT THE INVENTION

Examples, Reference Examples, Production Examples and PreparationExamples are shown below to specifically explain this invention.However, this invention should not be construed to be limited thereto.

Incidentally, the mixing ratios in eluants are all by volume, and as thecarriers in the column chromatography, there was used Silica Gel 60 (70to 230 mesh) (MERCK & CO., INC.) or BW-127ZH (manufactured by FujiSilicia Chemical Co., Ltd.).

Moreover, the abbreviation used has the following meaning:

TFA: Trifluoroacetic acid

EXAMPLE I-1

In 5 ml of toluene is dissolved 500 mg of(R)-5-bromo-2-(2,2-dimethylpropanoyl)-1-methyl-isoindoline, and theretoare added successively 510 mg of triethylamine, 35 mg ofbis(triphenylphosphine)palladium(II) chloride and 330 mg of4,4,5,5-tetramethyl-1,3,2-dioxaborolane. Thereafter, the resultingmixture is heated under reflux for 5 hours in a nitrogen atmosphere.Subsequently, to the reaction mixture are added 480 mg of ethyl7-bromo-1-cyclopropyl-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate,360 mg of sodium carbonate and 35 mg ofbis(triphenylphosphine)palladium(II) chloride and then the resultingmixture is heated under reflux for 3 hours in a nitrogen atmosphere. Thereaction mixture is added to a mixed solvent of 20 ml of ethyl acetateand 10 ml of water and the organic layer is separated. The organic layerseparated is washed with saturated saline and then dried over anhydrousmagnesium sulfate. The solvent is removed by distillation under reducedpressure and the residue obtained is purified by a silica gel columnchromatography (eluant; hexane:ethyl acetate=1:2) to obtain 470 mg ofethyl(R)-1-cyclopropyl-8-difluoromethoxy-7-[2-(2,2-dimethylpropanoyl)-1-methyl-2,3-dihydro-1H-isoindolin-5-yl]-4-oxo-1,4-dihydro-3-quinolinecarboxylate.

IR (KBr) cm⁻¹: 1730, 1610

NMR (CDCl₃)δvalue: 0.85-1.45 (4H, m), 1.37(9H, s), 1.40(3H, d, J=6.0Hz), 1.50(3H, t, J=7.0 Hz), 4.12(1H, m), 4.41(2H, q, J=7.0 Hz), 4.95(1H,d, J=12.0 Hz), 5.08(1H, d, J=12.0 Hz), 5.50(1H, q, J=6.0 Hz), 5.90(1H,t, J=76.0 Hz), 7.39(1H, d, J=8.0 Hz), 7.41(1H, d, J=8.0 Hz), 7.49(1H,s), 7.54(1H, d, J=8.0 Hz), 8.45(1H, d, J=8.0 Hz), 8.69(1H, s)

EXAMPLE I-2

In 10 ml of dioxane is dissolved 1 g of(R)-5-bromo-2-(2,2-dimethylpropanoyl)-1-methyl-isoindoline and theretoare added successively 1.02 g of triethylamine,1,1′-bis(diphenylphosphino)ferrocenepalladium(II) chloride and 650 mg of4,4,5,5-tetramethyl-1,3,2-dioxoborolane, after which the resultingmixture is heated under reflux for 2 hours in an nitrogen atmosphere.The reaction mixture is added to a mixed solvent of 30 ml of ethylacetate and 20 ml of water and the pH is adjusted to 2 with 2moles/liter hydrochloric acid, after which the organic layer isseparated. The organic layer separated is washed with saturated salineand then dried over anhydrous magnesium sulfate. The solvent is removedby distillation under reduced pressure, and the residue obtained ispurified by a silica gel column chromatography (eluant; hexane:ethylacetate=5:1) to obtain 400 mg of(R)-2-(2,2-dimethylpropanoyl)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)isoindoline.

IR (KBr) cm⁻¹: 1740, 1620, 1360, 1145

NMR (CDCl₃) δvalue: 1.33(9H, s), 1.35(12H, s), 1.46(3H, d, J=6.0 Hz),4.93(1H, d, J=12.0 Hz), 5.00(1H, d, J=12.0 Hz), 5.46(1H, q, J=6.0 Hz),7.25(1H, d, J=7.0 Hz), 7.71(1H, s), 7.75(1H, d, J=7.0 Hz)

EXAMPLE I-3

In 3 ml of dimethyl sulfoxide is dissolved 200 mg of(R)-5-bromo-2-(2,2-dimethylpropanoyl)-1-methyl-isoindoline and theretoare added successively 200 mg of potassium acetate, 14 mg ofbis(triphenylphosphine)palladium(II) chloride and 170 mg of4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl-4′,4′,5′,5′-tetramethyl-1′,3′,2′-dioxaborolane,after which the resulting mixture is heated under reflux for 5 hours ina nitrogen atmosphere. The reaction mixture is added to a mixed solventof 10 ml of ethyl acetate and 10 ml of water and then the pH is adjustedto 2 with 2 moles/liter hydrochloric acid, after which the organic layeris separated. The organic layer separated is washed with saturatedsaline and then dried over anhydrous magnesium sulfate. The solvent isremoved by distillation under reduced pressure and the residue obtainedis purified by a silica gel column chromatography (eluant; hexane:ethylacetate=5:1) to obtain 140 mg of(R)-2-(2,2-dimethylpropanoyl)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxoborolan-2-yl)isoindoline.

EXAMPLE I-4

In 15 ml of ethanol is dissolved 2.5 g of(R)-2-(2,2-dimethylpropanoyl)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindolineand thereto are added 2.8 g of ethyl7-bromo-1-cyclopropyl-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylateand 1.1 g of sodium carbonate. Subsequently, 150 mg of 10%palladium-activated carbon is added thereto under a nitrogen atmosphereand then heated under reflux for 3 hours in the same atmosphere. Aftercooling the reaction mixture, a mixed solvent of 15 ml of water and 30ml of acetone is added thereto, and the deposited crystals are collectedby filtration to obtain 3.6 g of ethyl(R)-1-cyclopropyl-8-difluoromethoxy-7-[2-(2,2-dimethylpropanoyl)-1-methyl-2,3-dihydro-1H-isoindolin-5-yl]-4-oxo-1,4-dihydro-3-quinolinecarboxylate.

Reference Example I-1

In 68 ml of conc. hydrochloric acid is suspended 34 g of ethyl1-cyclopropyl-8-difluoromethoxy-7-[2-(2,2-dimethylpropanoyl)-1-methyl-2,3-dihydro-1H-isoindolin-5-yl]-4-oxo-1,4-dihydro-3-quinolinecarboxylate,and the suspension is heated under reflux for 3 hours, after which 340ml of water is added thereto and then 170 ml of the solvent is removedby distillation under atmospheric pressure over 3 hours. After coolingthe reaction mixture, 17 ml of ethanol is added thereto and the crystalsdeposited are collected by filtration. The resulting(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-isoindolin-5-yl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid hydrochloride is suspended in 340 ml of water, and the suspensionis adjusted to pH 7.5 with 2 moles/liter sodium hydroxide solution withcooling, after which the crystals deposited are collected by filtrationto obtain 25.55 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-isoindolin-5-yl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid monohydrate.

Reference Example I-2

In 192 ml of 50% ethanol is suspended 24 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-isoindolin-5-yl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid monohydrate and the suspension is warmed to 40° C., after which5.71 g of methanesulfonic acid is added thereto to form a uniformsolution. Subsequently, 2.4 g of activated carbon is added to thesolution and the resulting mixture is stirred at the same temperaturefor 10 minutes and thereafter filtered. The filtrate is concentrated andthe deposited crystals are collected by filtration to obtain 26.64 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-isoindolin-5-yl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid methanesulfonate monohydrate.

Reference Example II-1

In 1,300 ml of water is dissolved 130 g of sodium hydroxide and in thesolution is suspended 188 g of (1R)-1-phenylethylamine, after which 287ml of pivaloyl chloride is dropwise added to the suspension at 20° C.over 40 minutes. The resulting mixture is stirred at the sametemperature for 1.5 hours and the crystals deposited are collected byfiltration to obtain 289 g ofN-[(1R)-1-phenylethyl]-2,2-dimethylpropanamide.

[α]_(D)=97 (29° C., c=1.0, CHCl₃)

IR (KBr) cm⁻¹:ν_(C═O) 1637

NMR (CDCl₃) δvalue: 1.20(9H,s), 1.48(3H, d, J=6.8 Hz), 5.11(1H, m),5.8(1H, brs), 7.31(5H, s)

EXAMPLE II-1

In 466 ml of tetrahydrofuran is dissolved 77.7 g ofN-[(1R)-1-phenylethyl]-2,2-dimethylpropanamide and to this solution isdropwise added 500 ml of a n-hexane solution of n-butyllithium (1.6 Msolution) at −30° C. over 30 minutes. After the dropwise addition, thetemperature of the resulting mixture is elevated to 0° C. and themixture is stirred at the same temperature for 1.5 hours and then cooledagain to −30° C., after which carbon dioxide is introduced into themixture. After the introduction, the reaction mixture is added to amixed solvent of 500 ml of ethyl acetate and 932 ml of water and theaqueous layer is separated. To the aqueous layer is added 200 ml ofmethylene chloride, and then the resulting aqueous layer is adjusted topH 3 with 6 N hydrochloric acid and then the organic layer is separated.The solvent is removed from the organic layer by distillation underreduced pressure and the residue thus obtained is dissolved in 310 ml ofmethanol. To this solution is added 72.6 g of methane-sulfonic acid andthe resulting mixture is heated under reflux for 3 hours and then cooledto 40° C., after which 777 ml of water is dropwise added to theresulting mixture and the crystals deposited are collected by filtrationto obtain 77.2 g of colorless crystals of methyl2-{(1R)-1-[(2,2-dimethylpropanoyl)amino]ethyl}benzoate.

[α]_(D)=52 (29° C., c=1.0, CHC1₃)

IR (KBr) cm⁻¹: ν_(C═O) 1722, 1639

NMR (CDCl₃) δvalue: 1.17(9H, s), 1.47(3H, d, J=7.1 Hz), 3.93(3H, s),5.4-5.6(1H, m), 7.1-7.6(4H, m), 7.86 (1H, dd, J=7.1, 1.2 Hz)

EXAMPLE II-2

In 560 ml of sulfuric acid is dissolved 70 g of methyl2-{(1R)-1-[(2,2-dimethylpropanoyl)amino]ethyl}benzoate and to thissolution is added 64.2 g of sodium N-bromoisocyanurate at 0° C., afterwhich the resulting mixture is stirred with ice-cooling for 3 hours. Thereaction mixture is added to a mixed solvent of 420 ml of methylenechloride and 1,050 ml of water and the insolubles are removed byfiltration and then the organic layer is separated. The organic layerobtained is washed with 0.5 N aqueous sodium hydroxide solution and thendried over anhydrous magnesium sulfate, after which the solvent isremoved by distillation under reduced pressure. The residue thusobtained is recrystallized from cyclohexane to obtain 74.2 g ofcolorless crystals of methyl5-bromo-2-{(1R)-1-[(2,2-dimethylpropanoyl)amino]ethyl}benzoate.

[α]_(D)=53 (29° C., c=1.0, CHCl₃)

IR (KBr) cm⁻¹: ν_(C═O) 1726, 1709, 1637

NMR (CDCl₃) δvalue: 1.16(9H, s), 1.45(3H, d, J=7.1 Hz), 3.93(3H, s),5.3-5.7(1H, m) 6.8-7.0(1H, m), 7.28(1H, d, J=8.3 Hz), 7.59(1H, dd,J=8.3, 2.2 Hz), 8.00(1H, d, J=2.2 Hz)

EXAMPLE II-3

In 420 ml of ethanol are suspended with ice-cooling 13.4 g of sodiumborohydride and 70.0 g of methyl5-bromo-2-{(1R)-1-[(2,2-dimethylpropanoyl)amino]ethyl}benzoate and tothe suspension is added 19.6 g of calcium chloride at 0° C., after whichthe resulting mixture is stirred with ice-cooling for 4 hours. Thereaction mixture is dropwise added to 359 ml of 1 N hydrochloric acidand then 840 ml of methylene chloride and 231 ml of water are addedthereto, after which the organic layer is separated. The organic layerobtained is washed with water and then dried over anhydrous magnesiumsulfate, after which the solvent is removed by distillation underreduced pressure. The residue obtained is dissolved 250 ml of diethyleneglycol dimethyl ether and thereto is added 32.4 ml of triethylamine,after which 16.7 ml of methanesulfonyl chloride is dropwise addedthereto with ice-cooling over 30 minutes. The resulting mixture isfurther stirred with ice-cooling for 30 minutes. The reaction mixture isdropwise added to 1,120 ml of water and the crystals deposited arecollected by filtration to obtain 70 g of colorless crystals of5-bromo-2-{1R)-1-[(2,2-dimethylpropanoyl)amino]ethyl}benzylmethanesulfonate.

[α]_(D)=26 (26° C., c−1.0 CHCl₃)

IR (KBr) cm⁻¹: ν_(C═O) 1646

NMR (CDCl₃) δvalue: 1.16(9H, s), 1.47(3H, d, J=6.8 Hz), 3.04(3H, s),5.0-5.3(1H, m), 5.22(1H, d, J=11.8 Hz), 5.60(1H, d, J=11.8 Hz),5.8-6.0(1H, m), 7.20(1H, d, J=9.0 Hz), 7.5-7.6(2H, m)

EXAMPLE II-4

In 200 ml of diethylene glycol dimethyl ether is dissolved 25 g of5-bromo-2-{(1R)-1-[(2,2-dimethylpropanoyl)amino]ethyl}benzylmethanesulfonate and to this solution is added 6.73 g of sodiumtert-butoxide at 0° C., after which the resulting mixture is stirred at5° C. for 2 hours. To the reaction mixture is dropwise added 150 ml ofwater and the crystals deposited are collected by filtration, to obtain16.9 g of colorless crystals of1-[(1R)-5-bromo-1-methyl-2,3-dihydro-1H-2-isoindolyl]-2,2-dimethyl-1-propanone.

[α]_(D)=92 (29° C., c=1.0, CHCl₃)

IR (KBr) cm⁻¹: ν_(C═O) 1616

NMR (CDCl₃) δvalue: 1.32(9H, s), 1.44(3H, d, J=6.4 Hz), 4.83(1H, d,J=14.5 Hz), 5.04(1H, d, J=14.5 Hz), 5.38 (1H, q, J=6.4 Hz), 7.0-7.5(3H,m)

EXAMPLE II-5

In 130 ml of 6 moles/liter hydrochloric acid, 16.5 g of1-[(1R)-5-bromo-1-methyl-2,3-dihydro-1H-2-isoinodolyl]-2,2-dimethyl-1-propanoneis heated under reflux for 5 hours. The reaction mixture is cooled toroom temperature, then washed with toluene and thereafter neutralizedwith 5 moles/liter aqueous sodium hydroxide solution, after which themixture is subjected to extraction with 81 ml of methylene chloride. Theextract is dried over anhydrous magnesium sulfate and thereto are added8 ml of triethylamine and then 15.25 g of trityl chloride, after whichthe resulting mixture is stirred at room temperature for 1 hour. Thereaction mixture is washed with water and then the solvent is removed bydistillation under reduced pressure, after which the residue thusobtained is recrystallized from isopropyl alcohol to obtain 16.7 g ofpale violet crystals of(1R)-5-bromo-1-methyl-2-trityl-2,3-dihydro-1H-isoindole.

[α]_(D)=92 (29° C., c=1.0, CHCl₃)

IR (KBr) cm⁻¹: ν_(C═O) 1596

NMR (CDCl₃) δvalue: 1.37(3H, d, J=6.4 Hz), 3.99(1H, d, J=16.8 Hz),4.3-4.6(2H, m), 6.5-7.6(18H, m)

EXAMPLE II-6

In 100 ml of toluene is dissolved 10.0 g of methyl5-bromo-2-{(1R)-1-[(2,2-dimethylpropanoyl)amino]ethyl}benzoate, and tothe solution is added 3.1 g of sodium tert-butoxide, after which theresulting mixture is stirred with ice-cooling for 15 minutes. Thereaction mixture is added to a mixed solvent of 150 ml of water and 100ml of ethyl acetate and the resulting mixture is neutralized with 2 Nhydrochloric acid, after which the organic layer is separated. Theorganic layer obtained is washed with saturated saline and then driedover anhydrous magnesium sulfate, after which the solvent is removed bydistillation under reduced pressure. The residue thus obtained isrecrystallized from isopropyl alcohol to obtain 5.7 g of colorlesscrystals of (3R)-6-bromo-3-methyl-2,3-dihydro-1H-1-isoindolone.

[α]_(D)=17.7 (29° C., c=1.0, CHCl₃)

IR (KBr) cm¹: ν_(C═O) 1702, 1655

NMR (CDCl₃) δvalue: 1.51(3H, d, J=6.8 Hz), 4.68(1H, q, J=6.8 Hz),7.31(1H, d, J=7.8 Hz), 7.69(1H, dd, J=7.8, 1.7 Hz), 7.95(1H, d, J=1.7Hz)

EXAMPLE II-7

In 1,200 ml of tetrahydrofuran are suspended with ice-cooling 60.3 g ofsodium borohydride and 40.0 g of(3R)-6-bromo-3-methyl-2,3-dihydro-1H-1-isoindolone, and to the resultingsuspension is added 301 g of boron trifluoride-diethyl ether complex at0° C., after which the resulting mixture is heated under reflux for 3hours. The reaction mixture is cooled and then added to a mixed solventof 2,000 ml of water and 700 ml of methylene chloride and the pH isadjusted to 10 with a 5 moles/liter aqueous sodium hydroxide solution,after which the organic layer is separated. The organic layer obtainedis washed with water and the solvent is removed by distillation underreduced pressure, after which the residue obtained is dissolved in 200ml of 6 moles/liter hydrochloric acid. To the solution is added 100 mlof toluene and the resulting mixture is heated under reflux for 5minutes. The reaction mixture is cooled and thereafter the aqueous layeris adjusted to pH 10 with 5 N aqueous sodium hydroxide solution and thensubjected to extraction with 200 ml of methylene chloride. The extractis dried over anhydrous magnesium sulfate and then the solvent isremoved by distillation under reduced pressure to obtain 30 g of a redoily product of (1R)-5-bromo-1-methyl-2,3-dihydro-1H-isoindole.

NMR (CDCl₃) δvalue: 1.41(3H, d, J=6.3 Hz), 2.27(1H, s), 3.8-4.6(3H, m),7.0-7.6(3H, m)

EXAMPLE II-8

In 120 ml of ethanol is dissolved 30 g of(1R)-5-bromo-1-methyl-2,3-dihydro-1H-isoindole, and 12 ml of conc.hydrochloric acid is added to the solution, after which the solvent isremoved by distillation under reduced pressure. The residue thusobtained is recrystallized from isopropyl alcohol to obtain 27.7 g ofred crystals of (1R)-5-bromo-1-methyl-2,3-dihydro-1H-isoindolehydrochloride.

[α]_(D)=12.8 (27° C., c=1.00, CHCl₃)

IR (KBr) cm⁻¹: 1602, 1593

EXAMPLE II-9

In 32 ml of methylene chloride is suspended 3.2 g of(1R)-5-bromo-1-methyl-2,3-dihydro-1H-isoindole hydrochloride and to thesuspension is added 3.94 ml of triethylamine, after which a solution of3.95 g of trityl chloride in 10 ml of methylene chloride is addedthereto and the resulting mixture is stirred at room temperature for 2hours. The reaction mixture is washed with water and then the solvent isremoved by distillation under reduced pressure, after which the residuethus obtained is recrystallized from isopropyl alcohol to obtain 4.83 gof pale violet crystals of(1R)-5-bromo-1-methyl-2-trityl-2,3-dihydro-1H-isoindole. The physicalproperty values of this compound were identical with those of thecompound obtained in Examples II-5.

EXAMPLE II-10

In 67.5 ml of tetrahydrofuran is dissolved 13.5 g of(1R)-5-bromo-1-methyl-2-trityl-2,3-dihydro-1H-isoindole and to thissolution is dropwise added 19.7 ml of an n-hexane solution ofn-butyllithium (1.66 M solution) at −50° C. over 10 minutes. At the sametemperature, the resulting mixture is stirred for 45 minutes andthereafter 5.87 g of triisopropyl borate is dropwise added thereto over15 minutes, after which the resulting mixture is further stirred at thesame temperature for 1 hour. The reaction mixture is added to 67.5 ml ofwater and the resulting mixture is stirred at 10° C. for 1 hour and thenadjusted to pH 7 with acetic acid, after which the organic layer isseparated and dried over anhydrous magnesium sulfate. Thereafter, thesolvent is removed from the dried layer by distillation under reducedpressure. The residue thus obtained is recrystallized from cyclohexaneto obtain 8.6 g of brownish gray crystals of(1R)-1-methyl-2-trityl-2,3-dihydro-1H-5-isoindolylboronic acid.

[α]_(D)=59 (28° C., c=1.0, CHCl₃)

IR (KBr) cm⁻¹: ν_(B—O) 1356

NMR (CDCl₃) δvalue: 1.40(3H, d, J=6.3 Hz), 4.1-4.8 (3H, m), 6.6-7.8(18H,m)

EXAMPLE II-11

In a mixed solvent of 4 ml of tetrahydrofuran and 1.5 ml of hexane issuspended 1 g of(1R)-1-methyl-2-trityl-2,3-dihydro-1H-5-isoindolylboronic acid and then0.24 g of diethanolamine is added to the suspension, after which theresulting mixture is stirred for 20 minutes. The crystals deposited arecollected by filtration to obtain 0.88 g of colorless crystals of2-[(1R)-1-methyl-2-trityl-2,3-dihydro-1H-5-isoindolyl]-1,3,6,2-dioxazaborocane.

[α]_(D)=57.2 (25° C., c=0.33, CHCl₃)

IR (KBr) cm⁻¹: 1490, 1446

NMR (CDCl₃) δvalue: 1.18(3H, d, J=6.1 Hz), 2.4-4.6 (12H, m), 6.5-7.8(18H, m)

Production Example II-1

In a mixed solvent of 2 ml of water and 5 ml of ethyl acetate issuspended 1.34 g of2-[(1R)-1-methyl-2-trityl-2,3-dihydro-1H-5-isoindolyl]-1,3,6,2-dioxazaborocaneand to this suspension are added 1.0 g of ethyl7-bromo-1-cyclopropyl-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate,0.55 g of sodium carbonate and 0.05 g ofbis(triphenylphosphine)palladium(II) chloride, after which the resultingmixture is heated under reflux for 3 hours in a nitrogen atmosphere. Thereaction mixture is added to a mixed solvent of 10 ml of methylenechloride and 10 ml of water, and the organic layer is separated. Theorganic layer obtained is washed with saturated saline and then driedover anhydrous magnesium sulfate, after which the solvent is removed bydistillation under reduced pressure. The residue thus obtained isrecrystallized from ethanol to obtain 1.55 g of ethyl1-cyclopropyl-8-difluoromethoxy-7-[(1R)-1-methyl-2-trityl-2,3-dihydro-1H-5-isoindolyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylate.

[α]_(D)=32 (27° C., c=1.0, CHCl₃)

IR (KBr) cm⁻¹: ν_(C═O) 1734, 1690

NMR (CDCl₃) δvalue: 0.8-1.9(10H, m), 3.9-4.9(6H, m), 5.51(1H, t, J=75Hz), 6.7-8.0(19H, m), 8.35(1H, d, J=8.0 Hz), 8.66(1H, s)

Production Example II-2

In a mixed solvent of 50.6 ml of water and 50.6 ml of diethylene glycoldimethyl ether is suspended 13.5 g of2-[(1R)-1-methyl-2-trityl-2,3-dihydro-1H-5-isoindolyl]-1,3,6,2-dioxazaborocaneand to this suspension is added 1.58 ml of acetic acid, after which theresulting mixture is stirred for 30 minutes. To this mixture are furtheradded 10.1 g of ethyl7-bromo-1-cyclopropyl-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate,5.59 g of sodium carbonate and 0.088 g ofbis(triphenylphosphine)palladium(II) chloride, and the resulting mixtureis heated under reflux for 2 hours in a nitrogen atmosphere. Thereaction mixture is cooled to 40° C. and thereafter the organic layer isseparated. To the organic layer obtained is added 30 ml of ethanol andthe crystals deposited are collected by filtration to obtain 17.3 g ofethyl1-cyclopropyl-8-difluoromethoxy-7-[(1R)-1-methyl-2-trityl-2,3-dihydro-1H-5-isoindolyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylate.The physical property values of this compound were identical with thoseof the compound obtained in Production Example II-1.

EXAMPLE III-1

In 495 ml of water is dissolved 83.7 g of sodium hydroxide and to thissolution are added 165 g of R-(+)-1-(4-bromophenyl)ethylaminehydrochloride and 495 ml of isopropanol, after which 92.5 g of pivaloylchloride is dropwise added to the resulting solution at 20° C. over 1.5hours. At the same temperature, the resulting mixture is stirred for 30minutes, and thereafter, 660 ml of water is dropwise added to themixture over 30 minutes, after which the resulting mixture is cooled to10° C. The mixture is stirred at the same temperature for 1 hour andthereafter the deposits are collected by filtration to obtain 193.5 g(yield: 97.6%) of colorless crystals ofN-[(1R)-1-(4-bromophenyl)ethyl]-2,2-dimethylpropanamide.

Melting point: 132-134° C.

[α]_(D)+92° (25° C., c=1.0, CHCl₃)

IR (KBr) cm⁻¹: ν_(C═O) 1636

NMR (CDCl₃) δvalue: 1.19(9H, s), 1.45(3H, d, J=6.8 Hz), 4.90-5.20(1H,m), 5.70-6.00(1H, m), 7.16(2H, d, J=8.5 Hz), 7.45(2H, d, J=8.5 Hz)

EXAMPLE III-2

In 10 ml of tetrahydrofuran is dissolved 2 g ofN-[(1R)-1-(4-bromophenyl)ethyl]-2,2-dimethylpropanamide, and to thissolution is dropwise added 14.3 ml of phenyllithium (1.48 Mcyclohexane-diethyl ether solution), after which the temperature of theresulting mixture is elevated to −5° C. and the mixture is stirred atthe same temperature for 4 hours. Subsequently, 1.06 g ofparaformaldehyde is added thereto and the mixture is stirred at 5° C.for 1 hour, after which 6 ml of water is added to the reaction mixtureand the organic layer is separated. The organic layer obtained is driedover anhydrous magnesium sulfate and the solvent is removed bydistillation under reduced pressure. The residue obtained is purified bysilica gel chromatography (eluant; n-hexane:ethyl acetate=2:1) to obtain1.48 g (yield: 66.9%) of5-bromo-2-{(1R)-1-[(2,2-dimethylpropanoyl)amino]ethyl}benzyl alcohol.

IR (KBr) cm⁻¹: ν_(C═O) 1639, 1610

NMR (CDCl₃) δvalue: 1.14(9H, s), 1.46(3H, d, J=6.8 Hz), 4.3-5.4(4H, m),6.0-6.4(1H, m), 7.0-7.6(3H, m)

EXAMPLE III-3

In 135 ml of methylene chloride is dissolved 13.50 g of5-bromo-2-{(1R)-1-[(2,2-dimethylpropanoyl)amino]ethyl}benzyl alcohol,and to this solution are added with ice-cooling 6.59 ml of triethylamineand 3.66 ml of methanesulfonyl chloride, after which the resultingmixture is stirred with ice-cooling for 1 hour. Subsequently, 50 ml ofwater is added to the reaction mixture and the pH is adjusted to 2.0with 2 moles/liter hydrochloric acid and thereafter the organic layer isseparated. The organic layer obtained is washed with water and thendried over anhydrous magnesium sulfate, after which the solvent isremoved by distillation under reduced pressure. To the residue obtainedare added 50 ml of toluene and 50 ml of cyclohexane, and the depositsare collected by filtration to obtain 11.5 g (yield: 68.2%) of colorlesscrystals of 5-bromo-2-{(1R)-1-[(2,2-dimethylpropanoyl)amino]ethyl}benzylmethanesulfonate.

[α]_(D)+26° (25° C., c=1.0, CHCl₃)

IR (KBr) cm⁻¹: νC═O 1646

NMR (CDCl₃) δvalue: 1.16(9H, s), 1.47(3H, d, J=6.8 Hz), 3.04(3H, s),5.0-5.3(1H, m), 5.22(1H, d, J=11.8 Hz), 5.60(1H, d, J=11.8 Hz),5.8-6.0(1H, m), 7.20(1H, d, J=9.0 Hz), 7.5-7.6(2H, m)

EXAMPLE III-4

In 225 ml of tetrahydrofuran is dissolved 45 g ofN-[(1R)-1-(4-bromophenyl)ethyl]-2,2-dimethylpropanamide, and to thissolution is dropwise added 505 ml of phenyllithium (0.94 Mcyclohexane-diethyl ether solution) at −30° C., after which thetemperature of the mixture is elevated to −5° C. and the mixture isstirred at the same temperature for 3 hours. Subsequently, 23.77 g ofparaformaldehyde is added to the mixture and the resulting mixture isstirred at 5° C. for 1 hour, after which 180 ml of water is added to thereaction mixture and the organic layer is separated. The organic layerobtained is washed with saturated saline and then dried over Zeolum 4A(manufactured by TOSOH CORP.), after which Zeolum 4A is removed byfiltration. To the filtrate obtained is added 43.26 g of triethylamineand the resulting mixture is cooled to 10° C., after which 31.07 g ofacetyl chloride is dropwise added to the mixture over 30 minutes. Theresulting mixture is stirred at the same temperature for 25 minutes.Subsequently, 180 ml of water is added to the reaction mixture and thenthe pH is adjusted to 2.0 with 2 moles/liter hydrochloric acid, afterwhich the organic layer is separated. The organic layer obtained iswashed successively with 5% (w/w) sodium hydrogencarbonate and water,and thereafter, the solvent is removed by distillation under atmosphericpressure. To the residue obtained are added 113 ml of cyclohexane and135 ml of n-hexane and the deposits are collected by filtration toobtain 33.93 g (yield: 60.1%) of colorless crystals of5-bromo-2-{(1R)-1-[(2,2-dimethylpropanoyl)amino]ethyl}benzyl acetate.

Melting point: 109-112.5° C.

IR (KBr) cm⁻¹: ν_(C═O) 1750, 1734, 1635

NMR (CDCl₃) δvalue: 1.17(9H, s), 1.45(3H, d, J=6.8 Hz), 2.10(3H, s),4.90-5.50(3H, m), 5.70-6.10(1H, m), 7.10-7.60(3H, m)

EXAMPLE III-5

In 20 ml of tetrahydrofuran is dissolved 4.0 g ofN-[(1R)-1-(4-bromophenyl)ethyl]-2,2-dimethylpropanamide, and to thissolution is dropwise added 45 ml of phenyllithium (0.94 Mcyclohexane-diethyl ether solution) at −30° C., after which thetemperature of the resulting mixture is elevated to −5° C. and themixture is stirred at the same temperature for 2 hours. Subsequently,1.69 g of paraformaldehyde is added to the mixture and the resultingmixture is stirred at 5° C. for 1 hour, after which 160 ml of water isadded to the reaction mixture and the organic layer is separated. Theorganic layer obtained is washed with saturated saline and then driedwith Zeolum 4A, after which Zeolum 4A is removed from the layer byfiltration. The filtrate obtained is cooled to −15° C. and then 2.10 mlof thionyl chloride is added to the filtrate, after which thetemperature of the resulting mixture is elevated to room temperature andthe mixture is stirred at the same temperature for 1 hour. Subsequently,8 ml of water is added to the reaction mixture and the pH is adjusted to5.5 with 5 moles/liter sodium hydroxide solution, after which theorganic layer is separated. The organic layer obtained is subjected toremoval of the solvent by distillation under atmospheric pressure and tothe residue obtained are added 12 ml of cyclohexane and 12 ml ofn-hexane and then the deposits are collected by filtration to obtain2.43 g (yield 52.0%) of colorless crystals of5-bromo-2-{(1R)-1-[(2,2-dimethylpropanoyl)amino]ethyl}benzyl chloride.

IR (KBr) cm⁻¹: ν_(C═O) 1634

NMR (CDCl₃) δvalue: 1.16(9H, s), 1.49(3H, d, J=6.8 Hz), 4.48(1H, d,J=11.7 Hz), 5.07(1H, d, J=11.7 Hz), 5.00-5.40(1H, m), 5.70-6.10(1H, m),7.10-7.60(3H, m)

EXAMPLE III-6

To a mixed solution of 30 g of a 50% (w/w) aqueous sodium hydroxidesolution and 40 ml of toluene are added 10 g of5-bromo-2-{(1R)-1-[(2,2-dimethylpropanoyl)amino]ethyl}benzyl acetate and0.27 g of tetra-n-butylammonium bromide at room temperature, and thetemperature of the resulting mixture is elevated to 35° C., after whichthe mixture is stirred for 1 hour. The mixture is cooled to roomtemperature and thereafter 30 ml of water is added to the reactionmixture, after which the organic layer is separated. The organic layeris dried over anhydrous magnesium sulfate and then the anhydrousmagnesium sulfate is removed by filtration. To the filtrate obtained isadded 3.98 g of triethylamine and the resulting mixture is cooled to 10°C., after which 3.86 g of methanesulfonyl chloride is dropwise addedthereto over 10 minutes. At the same temperature, the mixture is stirredfor 30 minutes and thereafter 30 ml of water is added to the reactionmixture, after which the organic layer is separated. To the organiclayer obtained is added 30 g of a 50% (w/w) aqueous sodium hydroxidesolution and the temperature of the resulting mixture is elevated to 35°C., after which 0.27 g of tetra-n-butylammonium bromide is addedthereto. The mixture is stirred at the same temperature for 1 hour and35 minutes and then cooled to room temperature, after which 30 ml ofwater is added to the reaction mixture and the organic layer isseparated. The organic layer separated is washed with water andthereafter the solvent is removed by distillation under reducedpressure, after which to the residue obtained are added 10 ml ofethylene glycol and 20 ml of conc. hydrochloric acid. The resultingmixture is heated under reflux for 4 hours. After cooling, to thereaction mixture are added 40 ml of water and 20 ml of toluene and thenthe aqueous layer is separated. The aqueous layer obtained is treatedwith active carbon and thereto is then added 40 ml of methylenechloride, after which the pH is adjusted to 11 with 20% (w/w) aqueoussodium hydroxide solution. Subsequently, the organic layer is separatedand dried over anhydrous magnesium sulfate and thereafter to the organiclayer is added 2.98 g of triethylamine, after which the resultingmixture is cooled to −15° C. and then 7.43 g of trityl chloride is addedthereto. The temperature of the reaction mixture is elevated to roomtemperature and the mixture is stirred at room temperature for 30minutes, after which 20 ml of water is added thereto and the organiclayer is separated. The organic layer separated is subjected to removalof the solvent by distillation under atmospheric pressure and 45 ml ofisopropanol is added to the residue obtained, after which the depositswere collected by filtration to obtain 10.11 g (yield: 79.0%) of paleviolet crystals of (1R)-5-10bromo-1-methyl-2-trityl-2,3-dihydro-1H-isoindole.

[α]_(D)+92°(25° C., c=1.0, CHCl₃)

IR (KBr) cm⁻¹: 1596

NMR (CDCl₃) δvalue: 1.37(3H, d, J=6.4 Hz), 3.99(1H, d, J=16.8 Hz),4.3-4.6(2H, m), 6.5-7.6(18H, m)

EXAMPLE III-7

The same ring-closing reaction as in Example III-6 is repeated byreplacing the5-bromo-2-{(1R)-1-[(2,2-dimethylpropanoyl)amino]ethyl}benzyl acetate by5-bromo-2-{(1R)-1-[(2,2-dimethylpropanoyl)amino]ethyl}benzyl chloride toobtain (1R)-5-bromo-1-methyl-2-trityl-2,3-dihydro-1H-isoindole.

EXAMPLE III-8

In 230 ml of tetrahydrofuran is dissolved 46 g ofN-[(1R)-1-(4-bromophenyl)ethyl]-2,2-dimethylpropanamide, and to thissolution is dropwise added 300 ml of phenyllithium (1.62 Mcyclohexane-diethyl ether solution) at −35° C. and the temperature ofthe resulting mixture is elevated to −5° C., after which the mixture isstirred at the same temperature for 2 hours. Subsequently, 19.46 g ofparaformaldehyde is added to the mixture and the resulting mixture isstirred at 5° C. for 1 hour, after which 138 ml of water is added to thereaction mixture, and the organic layer is separated. The organic layerobtained is dried with Zeolum 4A and then Zeolum 4A is removed byfiltration. To the filtrate obtained are added 40.95 g of triethylamineand 37.10 g of methanesulfonyl chloride at 10° C. and the resultingmixture is stirred at the same temperature for 30 minutes. Subsequently,92 ml of water is added to the reaction mixture and the pH is adjustedto 2.5 with 6 moles/liter hydrochloric acid, after which the organiclayer is separated. To the organic layer separated are added 138 g of50% (w/w) aqueous sodium hydroxide solution and 4.6 g oftetra-n-butylammonium bromide and the resulting mixture is stirred at20° C. for 2 hours, after which 92 ml of water is added to the reactionmixture and the organic layer is separated. To the organic layerobtained is added 92 ml of water and the pH is adjusted to 3.0 with 6moles/liter hydrochloric acid, after which the solvent is removed bydistillation under atmospheric pressure. To the residue obtained areadded 46 ml of ethylene glycol and 92 ml of conc. hydrochloric acid, andthe resulting mixture is heated under reflux for 6 hours. After cooling,to the reaction mixture are added 138 ml of water and 92 ml of toluene,and the aqueous layer is separated. The aqueous layer is treated withactive carbon and thereafter 138 ml of methylene chloride is addedthereto, after which the pH is adjusted to 11 with 5 moles/liter aqueoussodium hydroxide solution. Subsequently, the organic layer is separatedand dried over Zeolum 4A. To the organic layer obtained is added 13.10 gof triethylamine and the resulting mixture is cooled to −15° C. and then31.59 g of trityl chloride is added thereto. The temperature of thereaction mixture is elevated to room temperature and the mixture isstirred at room temperature for 30 minutes, after which 138 ml of wateris added thereto and the organic layer is separated. The organic layerseparated is subjected to removal of the solvent by distillation underatmospheric pressure and to the residue obtained is added 207 ml ofisopropanol and the deposits are collected by filtration to obtain 42.5g (yield: 57.7%) of pale violet crystals of(1R)-5-bromo-1-methyl-2-trityl-2,3-dihydro-1H-isoindole. The physicalproperty values of this compound were identical with those of thecompound obtained in Example III-6.

Production Example III-1

In 67.5 ml of tetrahydrofuran is dissolved 13.5 g of(1R)-5-bromo-1-methyl-2-trityl-2,3-dihydro-1H-isoindole, and to thissolution is dropwise added 19.7 ml of an n-hexane solution ofn-butyllithium (1.66 M solution) at −50° C. over 10 minutes. At the sametemperature, the resulting mixture is stirred for 45 minutes andthereafter 5.87 g of triisopropyl borate is dropwise added to themixture over 15 minutes, after which the mixture is stirred at the sametemperature for 1 hour. The reaction mixture is added to 67.5 ml ofwater and the resulting mixture is stirred at 10° C. for 1 hour, afterwhich the pH is adjusted to 7 with acetic acid and the organic layer isseparated. The organic layer separated is dried over anhydrous magnesiumsulfate and thereafter the solvent is removed from the layer bydistillation under reduced pressure. The residue obtained isrecrystallized from cyclohexane to obtain 8.6 g of brownish graycrystals of (1R)-1-methyl-2-trityl-2,3-dihydro-1H-5-isoindolylboronicacid.

[α]_(D)+590 (28° C., c=1.0, CHCl₃)

IR (KBr) cm⁻¹: ν_(B═O) 1356

NMR (CDCl₃) δvalue: 1.40(3H, d, J=6.3 Hz), 4.1-4.8 (3H, m), 6.6-7.8(18H,m)

Production Example III-2

In a mixed solvent of 4 ml of tetrahydrofuran and 1.5 ml of hexane issuspended 1 g of(1R)-1-methyl-2-trityl-2,3-dihydro-1H-5-isoindolylboronic acid and then0.24 g of diethanolamine is added to the suspension, after which theresulting mixture is stirred for 20 minutes. The deposits are collectedby filtration to obtain 0.88 g of colorless crystals of2-[(1R)-1-methyl-2-trityl-2,3-dihydro-1H-5-isoindolyl]-1,3,6,2-dioxazaborocane.

[α]_(D) +57.20 (25° C., c=0.33, CHCl₃)

IR (KBr) cm⁻¹: 1490, 1446

NMR (CDCl₃) δvalue: 1.18(3H, d, J=6.1 Hz), 2.4-4.6 (12H, m),6.5-7.8(18H, m)

Production Example III-3

In a mixed solvent of 2 ml of water and 5 ml of ethyl acetate issuspended 1.34 g of2-[(1R)-1-methyl-2-trityl-2,3-dihydro-1H-5-isoindolyl]-13,6,2-dioxazaborocane and to this suspension are added 1.0 g of ethyl7-bromo-1-cyclopropyl-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate,0.55 g of sodium carbonate and 0.05 g ofbis(triphenylphosphine)palladium(II) chloride, after which the resultingmixture is heated under reflux for 3 hours in a nitrogen atmosphere. Thereaction mixture is added to a mixed solvent of 10 ml of methylenechloride and 10 ml of water and the organic layer is separated. Theorganic layer obtained is washed with saturated saline and then driedover anhydrous magnesium sulfate, after which the solvent is removedfrom the layer by distillation under reduced pressure. The residueobtained is recrystallized from ethanol to obtain 1.55 g of ethyl1-cyclopropyl-8-difluoromethoxy-7-[(1R)-1-methyl-2-trityl-2,3-dihydro-1H-5-isoindolyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylate.

[α]_(D)+320 (27° C., c=1.0, CHCl₃)

IR (KBr) cm⁻¹; ν_(C═O) 1734, 1690

NMR (CDCl₃) δvalue: 0.8-1.9(10H, m), 3.9-4.9(6H, m), 5.51(1H, t, J=75Hz), 6.7-8.0(19H, m), 8.35(1H, d, J=8.0 Hz), 8.66(1H, s)

Reference Example IV-1

To a mixed solvent of 193.3 g of bromine and 600 ml of methylenechloride is dropwise added 176.1 g of tert-butylamine at −20° C. over 1hour and the resulting mixture is stirred at the same temperature for 1hour, after which 100.0 g of ethyl m-hydroxybenzoate is added to themixture in 5 portions. The resulting mixture is stirred at the sametemperature for 2 hours, then at 0° C. for 1 hour and further at roomtemperature for 10 hours. The deposited matters are collected byfiltration and to the matters obtained are added 500 ml of ethyl acetateand 300 ml of 6 moles/liter hydrochloric acid, and the organic layer isseparated. The organic layer is washed with saturated saline and thendried over anhydrous magnesium sulfate, and the solvent is removed bydistillation under reduced pressure. The residue obtained is purified bydistillation under reduced pressure (135-142° C./0.5 mmHg) to obtain121.0 g of a colorless oily product of ethyl2,4-dibromo-3-hydroxybenzoate.

IR (KBr) cm⁻¹: ν_(C═O) 1722

NMR (CDCl₃) δvalue: 1.40(3H, t, J=7.1 Hz), 4.40(2H, q, J=7.1 Hz),6.39(1H, brs), 7.26(1H, d, J=8.3 Hz), 7.52 (1H, d, J=8.3 Hz)

EXAMPLE IV-1

To a mixed solution of 400 ml of a 35% aqueous sodium hydroxide solutionand 49.8 g of tetrabutylammonium bromide is added a solution of 100.0 gof ethyl 2,4-dibromo-3-hydroxybenzoate in 400 ml of toluene andthereafter 53.4 g of chlorodifluoromethane is blown into the resultingmixture at room temperature over 1 hour. To the reaction mixture isadded 400 ml of water and the organic layer is separated. The organiclayer obtained is washed with saturated saline and then dried overanhydrous magnesium sulfate, and the solvent is removed by distillationunder reduced pressure. The residue obtained is purified by a columnchromatography [eluant; n-hexane ethyl acetate=10:1] to obtain 110.8 gof colorless crystals of ethyl 2,4-dibromo-3-difluoromethoxybenzoate.

IR (KBr) cm⁻¹: νC═O 1727

NMR (CDCl₃) δvalue: 1.41(3H, t, J=7.1 Hz), 4.41(2H, q, J=7.1 Hz),6.65(1H, t, J=74.8 Hz), 7.48(1H, d, J=8.3 Hz), 7.66(1H, d, J=8.3 Hz)

EXAMPLE IV-2

In 10 ml of N,N-dimethylformamide is dissolved 10.0 g of ethyl2,4-dibromo-3-hydroxybenzoate and to the solution are added 4.5 g ofpotassium carbonate and then 100 ml of an N,N-dimethylformamide solutionof chlorodifluoromethane (10 M solution), after which the resultingmixture is stirred at 120-130° C. for 3 hours in a sealed tube. Thereaction mixture is added to a mixed solvent of 100 ml of ethyl acetateand 100 ml of water, and the pH is adjusted to 2 with 6 moles/literhydrochloric acid, after which the organic layer is separated. Theorganic layer obtained is washed with saturated saline and then driedover anhydrous magnesium sulfate, and the solvent is removed bydistillation under reduced pressure. The residue obtained is purified bya column chromatography [eluant; n-hexane:ethyl acetate=4:1] to obtain10.8 g of colorless crystals of ethyl2,4-dibromo-3-difluoro-methoxybenzoate.

IR (KBr) cm⁻¹: ν_(C═O) 1717

NMR (CDCl₃) δvalue: 6.68(1H, t, J=74.8 Hz), 7.60-7.90(2H, m), 8.83(1H,brs)

EXAMPLE IV-3

In 600 ml of methylene chloride is dissolved 100.0 g of2,4-dibromo-3-difluoromethoxybenzoic acid and thereto are added 21.6 gof imidazole and 96.5 g of triethylamine, after which 37.8 g of thionylchloride is added to the resulting mixture with ice-cooling. Theresulting mixture is stirred at the same temperature for 30 minutes andfurther at room temperature for 1 hour. Subsequently, 27.5 g ofmagnesium chloride, 29.3 g of triethylamine, 98.4 g of potassiummonoethyl malonate and 100 ml of N,N-dimethylformamide are addedsuccessively to the mixture and the resulting mixture is heated underreflux for 6 hours. To the reaction mixture is added 600 ml of water andthe pH is adjusted to 1 with 6 moles/liter hydrochloric acid, afterwhich the organic layer is separated. The organic layer obtained iswashed successively with a saturated aqueous sodium hydrogen-carbonatesolution, water and saturated saline, and thereafter, dried overanhydrous magnesium sulfate, after which the solvent is removed bydistillation under reduced pressure. The residue obtained is purified bya column chromatography [eluant; n-hexane:ethyl acetate=20:1] to obtain108.2 g of colorless crystals of ethyl2,4-dibromo-3-difluoromethoxybenzoyl acetate.

IR (KBr) cm⁻¹: ν_(C═O) 1670

NMR (CDCl₃) δvalue: 1.25(1.8H, t, J=7.1 Hz), 1.34 (1.2H, t, J=7.1 Hz),3.98(1.2H, s), 4.19(1.2H, q, J=7.1 Hz), 4.29(0.8H, q, J=7.1 Hz),5.40(0.4H, s), 6.65(1H, t, J=73.7 Hz), 7.25(1H, d, J=8.3 Hz), 7.65(0.6H,d, J=8.3 Hz), 7.69(0.4H, d, J=8.3 Hz), 12.41(0.4H, s)

EXAMPLE IV-4

In 600 ml of methylene chloride is dissolved 100.0 g of ethyl2,4-dibromo-3-difluoromethoxybenzoyl-acetate and to the solution areadded 31.9 g of acetic anhydride and 37.2 g of N,N-dimethylformamidedimethyl acetal, after which the resulting mixture is stirred at roomtemperature for 1 hour and the solvent is removed by distillation underreduced pressure. The residue obtained is dissolved in 500 ml ofisopropanol, and 14.8 g of cyclopropylamine is added thereto, afterwhich the resulting mixture is stirred at room temperature for 1 hour.The crystals deposited are collected by filtration to obtain 95.2 g ofcolorless crystals of ethyl2-(2,4-dibromo-3-difluoromethoxybenzoyl)-3-cyclopropylaminoacrylate.

IR (KBr) cm⁻¹: ν_(C═O) 1675, 1621

NMR (CDCl₃) δvalue: 0.60-1.20(7H, m), 2.80-3.20(1H, m), 3.96(2H, q,J=7.1 Hz), 6.61(1H, t, J=74.0 Hz), 6.92(1H, d, J=8.3 Hz), 7.58(1H, d,J=8.3 Hz), 8.28(0.8H, d, J=13.9 Hz), 8.37(0.2H, d, J=13.9 Hz),9.60-9.90(0.2H, m), 10.80-11.30(0.8H, m)

EXAMPLE IV-5

In 400 ml of dimethyl sulfoxide is dissolved 100.0 g of ethyl2-(2,4-dibromo-3-difluoromethoxybenzoyl)-3-cyclopropylaminoacrylate andthen 34.3 g of potassium carbonate is added thereto, after which theresulting mixture is stirred at 90° C. for 2 hours. The reaction mixtureis cooled to room temperature and thereafter 800 ml of water is addedthereto, after which the crystals deposited are collected by filtrationto obtain 78.3 g of colorless crystals of ethyl7-bromo-1-cyclopropyl-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate.

IR (KBr) cm⁻¹: ν_(C═O) 1687, 1640

NMR (CDCl₃) δvalue: 0.70-1.70(7H, m), 3.70-4.70(3H, m), 6.52(1H, t,J=74.5 Hz), 7.58(1H, d, J=8.5 Hz), 8.24(1H, d, J=8.5 Hz), 8.59(1H, s)

Production Example IV-1

In 15 ml of ethanol is dissolved 2.5 g of(R)-2-(2,2-dimethylpropanoyl)-1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isoindoline,and thereto are added 2.8 g of ethyl7-bromo-1-cyclopropyl-8-difluoromethoxy-1,4-dihydro-4-oxoquinoline-3-carboxylate and 1.1 g of sodium carbonate.Subsequently, 150 mg of 10% palladium-activated carbon is added to themixture in a nitrogen atmosphere and thereafter the resulting mixture isheated under reflux for 3 hours in the same atmosphere. The reactionmixture is cooled and thereafter added to a mixed solvent of 15 ml ofwater and 30 ml of acetone, and the crystals deposited are collected byfiltration to obtain 3.6 g of ethyl(R)-1-cyclopropyl-8-difluoromethoxy-7-[2-(2,2-dimethylpropanoyl)-1-methyl-2,3-dihydro-1H-5-isoindolyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylate.

Production Example IV-2

In 68 ml of conc. hydrochloric acid is suspended 34 g of ethyl(R)-1-cyclopropyl-8-difluoromethoxy-7-[2-(2,2-dimethylpropanoyl)-1-methyl-2,3-dihydro-1H-5-isoindolyl]-4-oxo-1,4-dihydro-3-quinolinecarboxylate,and the suspension is heated under reflux for 3 hours, after which 340ml of water is added to the resulting mixture and 170 ml of the solventis removed from the mixture by distillation under atmospheric pressureover 3 hours. The reaction mixture is cooled and thereafter 17 ml ofethanol is added to the mixture, after which the crystals deposited arecollected by filtration. The resulting(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid hydrochloride is suspended in 340 ml of water and the pH of themixture is adjusted to 7.5 with 2 moles/liter sodium hydroxide solution,after which the crystals deposited are collected by filtration to obtain25.55 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid monohydrate.

Production Example IV-3

In 192 ml of 50% ethanol is suspended 24 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid monohydrate, and the suspension is warmed to 40° C., after which5.71 g of methanesulfonic acid is added to form a uniform solution.Subsequently, 2.4 g of activated carbon is added and the resultingmixture is stirred at the same temperature for 10 minutes, after whichthe insolubles are removed by filtration. The filtrate is concentratedand the crystals deposited are collected by filtration to obtain 26.64 gof(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid methanesulfonate monohydrate.

EXAMPLE V-1

In 192 ml of 50% water-containing ethanol is suspended 24 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid and the suspension is warmed to 40° C., after which 5.71 g ofmethanesulfonic acid is added to the warmed suspension to form a uniformsolution. Subsequently, the solution is stirred at the same temperaturefor 10 minutes and thereafter filtered, and the filtrate isconcentrated, after which the crystals deposited are collected byfiltration to obtain 26.64 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid methanesulfonate monohydrate.

IR (KBr) cm⁻¹: ν_(C═O) 1724, 1615

NMR (TFA-d) δvalue: 1.2-2.1(7H, m), 3.16(3H, s), 4.7-5.7(4H, m),6.21(1H, t, J=72 Hz), 7.5-8.0(3H, m), 8.14(1H, d, J=10 Hz), 8.78(1H, d,J=10 Hz), 9.66 (1H, s)

Water content: 3.31%

EXAMPLE V-2

In 4 ml of ethanol is suspended 0.2 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid and then the suspension is warmed to 70° C., after which 45 mg ofmethanesulfonic acid is added to the warmed suspension to form a uniformsolution. Subsequently, the solution is stirred at the same temperaturefor 1 hour and then cooled to room temperature, after which the crystalsdeposited are collected by filtration to obtain 0.20 g of(R)-1-cyclo-propyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid methanesulfonate.

IR(KBr) cm⁻¹: μ_(C═O) 1716, 1613

NMR (TFA-d) δvalue: 1.2-2.1(7H, m), 3.16(3H, s), 4.6-5.6(4H, m),6.21(1H, t, J=73 Hz), 7.4-8.0(3H, m), 8.17(1H, d, J=10 Hz), 8.80(1H, d,J=10 Hz), 9.66(1H, s)

Water content: 0.1%

EXAMPLE V-3

In 2 ml of ethanol is suspended 0.2 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid methanesulfonate monohydrate and the suspension is stirred at roomtemperature for 15 hours, and then subjected to collection by filtrationto obtain 0.14 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid methanesulfonate.

The physical property values of the compound obtained above wereidentical with those of the compound obtained in Example V-2.

Water content: 0.33%

Reference Example V-1

In 10 ml of 50% water-containing ethanol is suspended 0.5 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid and the suspension is warmed to 50° C., after which 0.14 g ofphosphoric acid is added to the warmed suspension to form a uniformsolution. Subsequently, the solution is stirred at the same temperaturefor 10 minutes and then subjected to filtration. The filtrate is cooledto room temperature and then the crystals deposited are collected byfiltration to obtain 0.32 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinoline-carboxylicacid phosphate.

IR (KBr) cm⁻¹: ν_(C═O) 1722, 1616

NMR (TFA-d) δvalue: 1.1-2.1(7H, m), 4.5-5.6(4H, m), 6.20(1H, t, J=75Hz), 7.4-8.0(3H, m), 8.14(1H, d, J=10 Hz), 8.80(1H, d, J=10 Hz),9.65(1H, s)

Reference Example V-2

In 8.2 ml of 40% water-containing ethanol is suspended 0.7 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicand then 0.16 g of L-lactic acid is added thereto, after which theresulting mixture is warmed to 50° C. to form a uniform solution.Subsequently, the solution is subjected to filtration at the sametemperature and the filtrate is thereafter concentrated, and thecrystals deposited are collected by filtration to obtain 0.57 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid L-lactate.

IR (KBr) cm⁻¹: ν_(C═O) 1723, 1616

NMR (TFA-d) δvalue: 1.2-2.1(10H, m), 4.4-5.6(5H, m), 6.19(1H, t, J=72Hz), 7.5-8.0(3H, m), 8.14(1H, d, J=10 Hz), 8.79(1H, d, J=10 Hz),9.64(1H, s)

Reference Example V-3

In 9.4 ml of 25% water-containing ethanol is suspended 1.2 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid, and 2.57 ml of 1 mole/liter aqueous sodium hydroxide solution isadded thereto, after which the resulting mixture is exposed toultrasonic wave for 1 hour to form a uniform solution. Subsequently, thereaction mixture is washed twice with chloroform, and concentrated, andthe crystals deposited are collected by filtration to obtain 0.49 g ofsodium(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylate.

IR (KBr) cm⁻¹: νC═O 1636

NMR (TFA-d) δvalue: 1.2-2.1(7H, m), 4.6-5.6(4H, m), 6.20(1H, t, J=72Hz), 7.5-8.0(3H, m), 8.17(1H, d, J=10 Hz), 8.79(1H, d, J=10 Hz),9.66(1H, s)

Reference Example V-4

In 42 ml of 50% water-containing ethanol is suspended 0.2 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid and 0.11 g of citric acid is then added thereto, after which theresulting mixture is warmed to 65° C. to form a uniform solution.Subsequently, the solution is filtered at the same temperature and thefiltrate is concentrated, after which the crystals deposited arecollected by filtration to obtain 0.24 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid citrate.

IR (KBr) cm⁻¹: ν_(C═O) 1724, 1616

Reference Example V-5

In 0.75 ml of acetic acid is suspended 0.5 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1, 4-dihydro-3-quinolinecarboxylic acidand the suspension is warmed to 80° C. to form a uniform solution.Subsequently, the solution is filtered at the same temperature and then2.5 ml of ethanol is added to the filtrate, after which the crystalsdeposited are collected by filtration to obtain 0.24 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid acetate.

IR (KBr) cm⁻¹: ν_(C═O) 1723, 1622

NMR (TFA-d) δvalue: 1.2-2.1(7H, m), 2.28(3H, s), 4.7-5.6(4H, m),6.20(1H, t, J=74 Hz), 7.5-8.0(3H, m), 8.14(1H, d, J=10 Hz), 8.80(1H, d,J=10 Hz), 9.64(1H, s)

Reference Example V-6

In 20 ml of 50% water-containing ethanol is suspended 1.0 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid and the suspension is then warmed to 50° C., after which 0.41 ml of6 moles/liter hydrochloric acid is added thereto to form a uniformsolution. Subsequently, the solution is stirred at the same temperaturefor 10 minutes and then filtered. The filtrate is cooled to roomtemperature and the crystals deposited are thereafter collected byfiltration to obtain 0.56 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid hydrochloride.

IR (KBr) cm⁻¹: ν_(C═O) 1722, 1616

NMR (TFA-d) δvalue: 1.2-2.1(7H, m), 4.5-5.6(4H, m), 6.21(1H, t, J=73Hz), 7.5-8.0(3H, m), 8.15(1H, d, J=10 Hz), 8.78(1H, d, J=10 Hz),9.65(1H, s)

Reference Example V-7

In 12 ml of 20% water-containing ethanol is suspended 0.6 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid and 74 mg of magnesium ethoxide is then added thereto, after whichthe resulting mixture is heated under reflux for 2 hours. Subsequently,the reaction mixture is cooled to room temperature and thereafter thecrystals are collected by filtration to obtain 0.55 g of magnesium saltof(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid.

IR (KBr) cm⁻¹: ν_(C═O) 1612

NMR (TFA-d) δvalue: 1.1-2.1(7H, m), 4.5-5.6(4H, m), 6.20(1H, t, J=73Hz), 7.5-8.0(3H, m), 8.12(1H, d, J=10 Hz), 8.78(1H, d, J=10 Hz),9.65(1H, s)

Reference Example V-8

In 10 ml of 50% water-containing ethanol is suspended 0.5 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid and the suspension is then warmed to 50° C., after which 0.12 g ofsulfuric acid is added thereto to form a uniform solution. Subsequently,the solution is stirred at the same temperature for 10 minutes and thenfiltered. The filtrate is cooled to room temperature and thereafter thecrystals deposited are collected by filtration to obtain 0.34 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid sulfate.

IR (KBr) cm⁻¹: ν_(C═O) 1724, 1615

NMR (TFA-d) δvalue: 1.2-2.1(7H, m), 4.6-5.6(4H, m), 6.20(1H, t, J=73Hz), 7.5-8.0(3H, m), 8.12(1H, d, J=10 Hz), 8.80(1H, d, J=10 Hz),9.65(1H, s)

Preparation Example V-1

380.4 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid methanesulfonate monohydrate, 83.1 g of lactose, 36 g of cornstarch and 27 g of carboxymethyl starch sodium (Primojel, MatsutaniKagaku) are mixed, and the mixture is thereafter introduced into akneader (small size bench kneader, Koike Tekko) and then kneaded while180 g of a 6% aqueous hydroxypropyl cellulose solution (HPC-L, NipponSoda) is gradually added. The kneaded product is subjected to sizereduction by a power mill (PS-04S, Dalton, 2-mm herringbone screen) andthen dried by blowing air at 40° C. overnight. After the drying, theproduct is subjected to size reduction by a power mill (20-mesh squarescreen), and thereafter, 2.7 g of magnesium stearate is added theretoand mixed therewith to prepare a powder for tableting. This powder istableted by a rotary type tablet machine (HP-18, Hata Tekko) using apunch having a diameter of 7.5 mm so that the weight of one tabletbecomes 180 mg to obtain tablets each containing 100 mg of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid (as free base). This tablet is subjected to film coating in anaqueous system by conventional procedure (4 mg of hydroxypropylmethylcellulose (TC-5), 0.8 mg of Macrogol 6000, 0.4 mg of titanium oxide and0.4 mg of talc per tablet) to obtain a film-coated tablet.

Preparation Example V-2

Into 958 g of water for injection is introduced 6.338 g of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid methanesulfonate monohydrate while stirring to dissolve the latterin the former. To the solution are added 0.62 ml of 0.1 mole/litermethanesulfonic acid and 50 g of D-mannitol and the resulting mixture isfurther stirred. After the complete dissolution, the solution isfiltered through a 0.22-μm membrane filter. This filtrate is chargedinto vials in a proportion of 100 ml per vial and each of the vials isstopped with a rubber compound stopper and an aluminum cap andthereafter subjected to steam sterilization (121° C., 20 minutes) toobtain injections, each vial containing 500 mg of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid (as free base).

INDUSTRIAL APPLICABILITY

The production process of this invention is useful as a process for theindustrial production of a 7-isoindoline-quinolonecarboxylic acidderivative useful as an antibacterial agent, particularly T-3811 andisoindoline-5-boronic acid derivatives, 1-alkylisoindoline-5-boronicacid derivatives, 1-alkyl-5-halogenoisoindoline derivatives and7-bromo-quinolonecarboxylic acid derivatives which are intermediates forT-3811.

Moreover, t-3811 methanesulfonate is remarkably high in solubility at aphysiologically acceptable pH and further t-3811 methanesulfonatemonohydrate has no polymorphism and is good in stability againsthumidity and hence useful as the starting material for a compositioncomprising t-3811 as an active ingredient, particularly for a t-3811preparation.

What is claimed is:
 1. A process for producing a7-isoindolinequinolonecarboxylic acid derivative or its salt,represented by the general formula [1]:

wherein R¹ represents a hydrogen atom or a carboxyl-protecting group; R²represents a substituted or unsubstituted alkyl, alkenyl, cycloalkyl,aryl or heterocyclic group; R³ represents at least one group selectedfrom hydrogen atom, halogen atoms, substituted or unsubstituted alkyl,alkenyl, cycloalkyl, aryl, alkoxy or alkylthio groups, nitro group,cyano group, acyl groups, protected or unprotected hydroxyl groups orprotected or unprotected or substituted or unsubstituted amino groups;R⁴ represents at least one group selected from hydrogen atom, halogenatom, substituted or unsubstituted alkyl, alkenyl, cycloalkyl, aralkyl,aryl, alkoxy or alkylthio groups, protected or unprotected hydroxyl orimino groups, protected or unprotected or substituted or unsubstitutedamino groups, alkylidene groups, oxo group or groups each forming acycloalkane ring together with the carbon atom to which R⁴ bonds; R⁵represents a hydrogen atom, an amino-protecting group, a substituted orunsubstituted alkyl, cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl oraryl group; R⁶ represents a hydrogen atom, a halogen atom, a substitutedor unsubstituted alkyl, alkoxy or alkylthio group, a protected orunprotected hydroxyl or amino group or a nitro group; and A representsCH or C—R⁷ in which R⁷ represents a halogen atom, a substituted orunsubstituted alkyl, alkoxy or alkylthio group or a protected orunprotected hydroxyl group, comprising: reacting, in the presence ofmetallic palladium an isoindoline-5-boronic acid derivative representedby the following general formula [2] or its salt:

wherein R³, R⁴ and R⁵ have the same meanings as mentioned above; and R⁸and R⁹ represent hydrogen atoms or lower alkyl groups or form a ringcomprising the boron atom when taken together, with a 7-leavinggroup-substituted quinolonecarboxylic acid represented by the followinggeneral formula [3] or its salt:

wherein R¹, R², R⁶ and A have the same meanings as mentioned above; andX² represents a leaving group.
 2. A process for producing a7-isoindolinequinolonecarboxylic acid derivative or its salt accordingto claim 1, wherein the compound represented by the general formula [2]or its salt is a compound represented by the general formula [2b] or itssalt:

wherein R^(4a) represents an alkyl group; R⁵ represents a hydrogen atom,an amino-protecting group, a substituted or unsubstituted alkyl,cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl or aryl group; and R⁸ andR⁹ represent hydrogen atoms or lower alkyl groups or form a ringcomprising the boron atom when taken together, obtained by reacting aphenylalkylamine derivative represented by the general formula [10] orits salt:

wherein R^(4a) has the same meaning as mentioned above; and R^(5a)represents an amino-protecting group, a substituted or unsubstitutedalkyl, cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl or aryl group, withcarbon dioxide, a halogenated formic acid ester or a carbonic acid esterin the presence of a base to form a 2-aminoalkylbenzoic acid derivativerepresented by the general formula [9] or its salt:

wherein R^(4a) and R⁵ have the same meanings as mentioned above; and R¹⁰represents a hydrogen atom or a carboxyl-protecting group, subsequentlysubjecting the 2-aminoalkylbenzoic acid derivative or its salt tohalogenation reaction to obtain a 2-aminoalkyl-5-halogenobenzoic acidderivative represented by the general formula [8] or its salt:

wherein R^(4a), R⁵ and R¹⁰ have the same meanings as mentioned above;and X¹ represents a halogen atom, subsequently subjecting the2-aminoalkyl-5-halogenobenzoic acid derivative or is salt to reductionreaction to obtain a 2-aminoalkyl-5-halogenobenzyl alcohol derivativerepresented by the following general formula [6] or its salt:

wherein R^(4a), R⁵ and X¹ have the same meanings as mentioned above, andthereafter subjecting the 2-aminoalkyl-5-halogenobenzyl alcoholderivative or its salt to ring-closing reaction to obtain a1-alkyl-5-halogenoisoindoline derivative represented by the generalformula [4a] or its salt:

wherein R^(4a), R⁵ and X¹ have the same meanings as mentioned above andthen subjecting the 1-alkyl-5-halogenoisoindoline derivative or its saltto borodation, the compound represented by the general formula [3] orits salt is a compound represented by the general formula [3b] or itssalt:

wherein R¹, R², R⁶ and A have the same meanings as mentioned above andX³ represents a halogen atom, the compound represented by the generalformula [1a] or its salt is

wherein R^(4a), R¹, R², R⁵, R⁶ and A have the same meanings as mentionedabove.
 3. A process for producing a 7-isoindolinequinolonecarboxylicacid derivative or its salt according to claim 1, wherein the compoundrepresented by the general formula [2] or its salt is a compoundrepresented by the general formula [2b] or its salt:

wherein R^(4a) represents an alkyl group; R⁵ represents a hydrogen atom,an amino-protecting group, a substituted or unsubstituted alkyl,cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl or aryl group; and R⁸ andR⁹ represent hydrogen atoms or lower alkyl groups or form a ringcomprising the boron atom when taken together, obtained by reacting aphenylalkylamine derivative represented by the general formula [10] orits salt:

wherein R^(4a) has the same meaning as mentioned above; and R^(5a)represents an amino-protecting group, a substituted or unsubstitutedalkyl, cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl or aryl group, withcarbon dioxide, a halogenated formic acid ester or a carbonic acid esterin the presence of a base, to obtain a 2-aminoalkylbenzoic acidderivative represented by the general formula [9] or its salt:

wherein R^(4a) and R⁵ have the same meanings as mentioned above; and R¹⁰represents a hydrogen atom or a carboxyl-protecting group, subsequentlysubjecting the 2-aminoalkylbenzoic acid derivative or its salt tohalogenation reaction to obtain a 2-aminoalkyl-5-halogenobenzoic acidderivative represented by the general formula [8] or its salt:

wherein R^(4a), R⁵ and R¹⁰ have the same meanings as mentioned above;and X¹ represents a halogen atom, subsequently subjecting the2-aminoalkyl-5-halogenobenzoic acid derivative or is salt toring-closing reaction to obtain a 1-alkyl-3-oxo-5-halogenoisoindolinederivative represented by the general formula [7] or its salt:

wherein R^(4a), R⁵ and X¹ have the same meanings as mentioned above,subsequently subjecting the 1-alkyl-3-oxo-5-halogenoisoindolinederivative or its salt to reduction reaction to obtain a1-alkyl-5-halogenoisoindoline derivative represented by the generalformula [4a] or its salt:

wherein R^(4a), R⁵ and X¹ have the same meanings as mentioned above, andthen subjecting the 1-alkyl-5-halogenoisoindoline derivative or its saltto borodation, the compound represented by the general formula [3] orits salt is a compound represented by the general formula [3b] or itssalt:

wherein R¹, R², R⁶ and A have the same meanings as mentioned above andX³ represents a halogen atom, and the compound represented by thegeneral formula [1] or its salt is a compound represented by the generalformula [1a] or its salt:

wherein R^(4a), R¹, R², R⁵, R⁶ and A have the same meanings as mentionedabove.
 4. A process for producing a 7-isoindoline-quinolonecarboxylicacid derivative or its salt according to claim 1, wherein the compoundrepresented by the general formula [2] or its salt is a compoundrepresented by the general formula [2b] or its salt:

wherein R^(4a) represents an alkyl group; R⁵ represents a hydrogen atom,an amino-protecting group, a substituted or unsubstituted alkyl,cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl or aryl group; and R⁸ andR⁹ represent hydrogen atoms or lower alkyl groups or form a ringcomprising the boron atom when taken together, obtained by preparing acompound represented by the general formula [4a] or its salt

wherein R^(4a) represents an alkyl group; R⁵ represents a hydrogen atom,an amino-protecting group, a substituted or unsubstituted alkyl,cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl or aryl group; and X¹represents a halogen atom, obtained by reacting a 4-halogenobenzylaminederivative represented by the general formula [12] or its salt:

wherein R^(4a) and X¹ have the same meanings as mentioned above; andR^(5b), R^(5c) and R^(5d) may be the same or different and eachrepresents an alkyl group, with formaldehyde or its derivative in thepresence of an aryllithium to obtain a 2-aminoalkyl-5-halogenobenzylalcohol derivative represented by the general formula [6] or its salt;

wherein R^(4a), R⁵ and X¹ have the same meanings as mentioned above,subsequently introducing a leaving group thereinto to obtain a2-aminoalkyl-5-halogenobenzyl derivative represented by the generalformula [1] or its salt:

wherein R^(4a), R⁵ and X¹ have the same meanings as mentioned above; andY represents a leaving group, and subsequently subjecting the2-aminoalkyl-5-halogenobenzyl derivative to ring-closing reaction in thepresence of a base, and subjecting the compound represented by thegeneral formula [4a] or its salt to borodation, and the compoundrepresented by the general formula [1] or its salt is a compoundrepresented by the general formula [1a] or its salt:

wherein R^(4a), R¹, R², R⁵, R⁶ and A have the same meanings as mentionedabove.
 5. A process for producing a 7-isoindolinequinolonecarboxylicacid derivative or its salt according to claim 1, wherein the compoundrepresented by the general formula [3] or its salt is a compoundrepresented by the general formula [3a] or its salt:

wherein R^(1b) represents a carboxyl-protecting group; R^(2a) representsa substituted or unsubstituted alkyl, cycloalkyl, aryl or heterocyclicgroup; and R^(7a) represents a substituted or unsubstituted alkyl group,obtained by reacting a 2,4-dibromo-3-hydroxybenzoic acid esterrepresented by the general formula [13] or its salt:

wherein R^(1a) a represents a carboxyl-protecting group, with a compoundrepresented by the general formula [14]: R^(7a)—X  [14] wherein R^(7a)has the same meaning as mentioned above; and X represents a halogenatom, to obtain a 3-alkoxy-2,4-dibromobenzoic acid ester represented bythe general formula [15] or its salt:

wherein R^(1a) and R^(7a) have the same meanings as mentioned above,subsequently subjecting the 3-alkoxy-2,4-dibromobenzoic acid ester toelimination reaction of the carboxyl-protecting group to obtain a3-alkoxy-2,4-dibromobenzoic acid represented by the general formula [16]or its salt:

wherein R^(7a) has the same meaning as mentioned above, subsequentlysubjecting the 3-alkoxy-2,4-dibromobenzoic acid to ketoesterificationreaction to obtain a 3-alkoxy-2,4-dibromobenzoylacetic acid esterrepresented by the general formula [17] or its salt:

wherein R^(1b) represents a carboxyl-protecting group; and R^(7a) hasthe same meaning as mentioned above, subsequently reacting the3-alkoxy-2,4-dibromobenzoylacetic acid ester with an orthoester or anacetal, then reacting the reaction product with a compound representedby the general formula [18] or its salt: R^(2a)—NH  [18] wherein R^(2a)has the same meaning as mentioned above, to obtain a2-(3-alkoxy-2,4-dibromobenzoyl)-3-substituted aminoacrylic acid esterrepresented by the general formula [19] or its salt:

wherein R^(1b), R^(2a) and R^(7a) have the same meanings as mentionedabove, and thereafter subjecting the2-(3-alkoxy-2,4-dibromobenzoyl)-3-substituted aminoacrylic acid ester toring-closing reaction, and the compound represented by the generalformula [1] or its salt is a compound represented by the general formula[1b] or its salt:

wherein R¹, R^(2a), R³, R⁴, R⁵ and R^(7a) have the same meanings asmentioned above.
 6. A process for producing a7-isoindolinequinolonecarboxylic acid derivative or its salt accordingto claim 1, wherein R⁵ represents a hydrogen atom, a substituted orunsubstituted alkyl, cycloalkyl, alkylsulfonyl, arylsulfonyl, acyl oraryl group. 7.(R)-1-Cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid methanesulfonate. 8.(R)-1-Cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid methanesulfonate monohydrate.
 9. A composition comprising an activeingredient selected from the group consisting of(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid methanesulfonate and(R)-1-cyclopropyl-8-difluoromethoxy-7-(1-methyl-2,3-dihydro-1H-5-isoindolyl)-4-oxo-1,4-dihydro-3-quinolinecarboxylicacid methanesulfonate monohydrate, and an inactive ingredient.
 10. Thecomposition according to claim 9, wherein the inactive ingredient is acarrier acceptable as a preparation.
 11. A process for producing a7-isoindoline-quinolonecarboxylic acid derivative or its salt accordingto claim 1, wherein the compound represented by the general formula [2]or its salt is a compound represented by the general formula [2b] or itssalt, the compound represented by the general formula [3] or its salt isa compound represented by the general formula [3b] or its salt, and thecompound represented by the general formula or its salt is a compoundrepresented by the general formula [1a] or its salt.
 12. A process forproducing a 7-isoindoline-quinolonecarboxylic acid derivative or itssalt according to claim 1, wherein the compound represented by thegeneral formula [2] or its salt is a compound represented by the generalformula [2b] or its salt, the compound represented by the generalformula [3] or its salt is a compound represented by the general formula[3b] or its salt, and the compound represented by the general formula[1] or its salt is a compound represented by the general formula [1a] orits salt.
 13. A process for producing a7-isoindoline-quinolonecarboxylic acid derivative or its salt accordingto claim 1, wherein the compound represented by the general formula [2]or its salt is a compound represented by the general formula [2b] or itssalt obtained by preparing a compound represented by the general formula[4a] or its salt and subjecting the compound represented by the generalformula [4a] or its salt to borodation, and the compound represented bythe general formula [1] or its salt is a compound represented by thegeneral formula [1a] or its salt.
 14. A process for producing a7-isoindoline-quinolonecarboxylic acid derivative or its salt accordingto claim 1, wherein the compound represented by the general formula [3]or its salt is a compound represented by the general formula [3a] or itssalt, and the compound represented by the general formula [1] or itssalt is a compound represented by the general formula [1b] or its salt.